4-biarylyl-1-phenylazetidin-2-ones

ABSTRACT

4-Biarylyl-1-phenylazetidin-2-ones useful for the treatment of hypercholesterolemia are disclosed. The compounds are of the general formula 
     
       
         
         
             
             
         
       
     
     in which  
 
represents an aryl or heteroaryl residue; Ar represents an aryl residue; U is a two to six atom chain; and the R&#39;s represent substituents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is in part a divisional and in part a continuation ofcopending U.S. application Ser. No. 10/986,570, filed Nov. 10, 2004(allowed), which claimed priority from U.S. provisional application Ser.Nos. 60/518,698; 60/549,577; 60/592,529; and 60/614,005, filed Nov. 10,2003; Mar. 3, 2004; Jul. 30, 2004; and Sep. 28, 2004, respectively. Theentire disclosures of all are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to a chemical genus of4-biarylyl-1-phenylazetidin-2-ones useful for the treatment ofhypercholesterolemia and cholesterol-associated benign and malignanttumors.

BACKGROUND OF THE INVENTION

1,4-Diphenylazetidin-2-ones and their utility for treating disorders oflipid metabolism are described in U.S. Pat. No. 6,498,156, U.S. RE37721and PCT application WO02/50027, the disclosures of which areincorporated herein by reference as they relate to utility.

SUMMARY OF THE INVENTION

In one aspect the invention relates to compounds of formula:

which comprises compounds of two closely related genera, Φ and Ψ:

wherein

represents an aryl or heteroaryl residue; Ar represents an aryl residue;R¹ represents one, two, three, four or five residues chosenindependently from H, halogen, —OH, loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃,CF₂H, CH₂F, —O-loweralkyl, methylenedioxy, ethylenedioxy,hydroxyloweralkyl, —CN, CF₃, nitro, —SH, —S-loweralkyl, amino,alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino,amidino, phenyl, benzyl, phenoxy, benzyloxy, —PO₃H₂, —SO₃H, —B(OH)₂, asugar, a polyol, a glucuronide and a sugar carbamate; R² represents one,two, three, four or five residues chosen independently from H, halogen,—OH, loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃, CF₂H, CH₂F, —O-loweralkyl,methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —SH,—S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido,alkylsulfoxide, acylamino, amidino, —PO₃H₂, —SO₃H, —B(OH)₂, a sugar, apolyol, a glucuronide and a sugar carbamate; R⁴ represents one, two,three or four residues chosen independently from H, halogen, —OH,loweralkyl, —O-loweralkyl, hydroxyloweralkyl, —CN, CF₃, nitro, —SH,—S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido,alkylsulfoxide, acylamino, amidino, —PO₃H₂, —SO₃H, —B(OH)₂, a sugar, apolyol, a glucuronide and a sugar carbamate; R^(4f) is —OH, —SH or—B(OH)₂; R^(5g) represents one, two, three, four or five residues on Archosen independently from halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, ethylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —SH,—S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido,alkylsulfoxide, acylamino, amidino, —PO₃H₂, —SO₃H, —B(OH)₂, a sugar, apolyol, a glucuronide and a sugar carbamate; R^(5h) represents one, two,three, four or five residues on Ar chosen independently from hydrogen,halogen, —OH, loweralkyl, —O-loweralkyl, methylenedioxy, ethylenedioxy,hydroxyloweralkyl, —CN, CF₃, nitro, —SH, —S-loweralkyl, amino,alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino,amidino, —PO₃H₂, —SO₃H, —B(OH)₂, a sugar, a polyol, a glucuronide and asugar carbamate; U is (C₂-C₆)-alkylene in which one or more —CH₂— may bereplaced by a radical chosen from —S—, —S(O)—, —SO₂—, —O—, —C(═O)—,—CHOH—, —NH—, CHF, CF₂, —CH(O-loweralkyl)-, —CH(O-loweracyl)-,—CH(OSO₃H)—, —CH(OPO₃H₂)—, —CH(OB(OH)₂)—, or —NOH—, with the provisosthat (1) adjacent —CH₂— residues are not replaced by —S—, —S(O)—, —SO₂—or —O—; and (2) —S—, —S(O)—, —SO₂—, —O— and —NH— residues are notseparated only by a single carbon; U^(a) is the same as U except thatU^(a) excludes —CH₂CH₂CH(OH)—.The genera Φ and Ψ exclude compounds in which R^(5g) is —CN;2,5-dimethoxy; 2,6-dimethoxy or halogen when neither ring of thebiphenyl residue is further substituted. The genera Φ and Ψ also excludecompounds in which R^(5g) is 2-hydroxy when

represents a 2,5-thienyl residue.

Subgenera include biphenyl compounds of general formulae I-VII:

In formula I, R¹ and R² represent one or two residues chosenindependently from H, halogen, —OH, loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃,CF₂H, CH₂F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF₃,nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino,amidino, phenyl, benzyl, phenoxy, benzyloxy, a sugar, a glucuronide anda sugar carbamate; R³ is chosen from H, —OH, fluoro, —O-loweralkyl and—O-acyl; R⁴ represents one, two, three or four residues chosenindependently from H, halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy, a sugar, a glucuronide and a sugarcarbamate; R^(5f) represents one, two, three, four or five residueschosen independently from halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy, a sugar, a glucuronide a sugar carbamate and—N⁺R⁶R⁷R⁸X⁻; R⁶ is C₁ to C₂₀ hydrocarbon or forms a five- toseven-membered ring with R⁷; R⁷ is alkyl or forms a five- toseven-membered ring with R⁶; R⁸ is alkyl or together with R⁶ or R⁷ formsa second five- to seven-membered ring; and X is an anion.

In formula II one of R^(1a), R^(4a) and R^(5a) is -Q-A-N⁺R⁹R¹⁰R¹¹X⁻ andthe other two of R^(1a), R^(4a) and R^(5a) are chosen independently fromhydrogen, halogen, —OH, loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃, CF₂H, CH₂F,—O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro,—S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino,amidino, phenyl, benzyl, phenoxy, benzyloxy. R^(2a) represents one ortwo residues chosen independently from H, halogen, —OH, loweralkyl,OCH₃, OCF₂H, OCF₃, CH₃, CF₂H, CH₂F, —O-loweralkyl, methylenedioxy,hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl, amino, alkylamino,dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido,alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy andbenzyloxy. R³ is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl.Q is chosen from a direct bond, —O—, —S—, —NH—, —CH₂O—, —CH₂NH—,—C(═O)—, —CONH—, —NHCO—, —O(C═O)—, —(C═O)O—, —NHCONH—, —OCONH— and—NHCOO—. A is chosen from C₂ to C₂₀ hydrocarbon, substituted alkyl of 2to 20 carbons, substituted aryl, substituted arylalkyl, and oxaalkyl offour to fifty carbons; and, when Q is a direct bond, —C(═O) or —O(C═O)—,A may additionally be methylene. R⁹ is C₁ to C₂₀ hydrocarbon or forms afive- to seven-membered ring with A or R¹⁰; R¹⁰ is alkyl, forms a doublebond with A or forms a five- to seven-membered ring with R⁹; R¹¹ isalkyl or together with R¹⁰ or R⁹ forms a second five- to seven-memberedring; and X is an anion.

In formula III, R^(2b) represents one or two residues chosenindependently from H, halogen, —OH, loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃,CF₂H, CH₂F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF₃,nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino,amidino, phenyl, benzyl, phenoxy, benzyloxy. R³ is chosen from H, —OH,fluoro, —O-loweralkyl and —O-acyl. One of R^(1b), R^(4b) and R^(5b) isR¹² and the other two of R^(1b), R^(4b) and R^(5b) are chosenindependently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy, a sugar, a glucuronide, and a sugarcarbamate; R¹² is (C₀ to C₃₀)alkylene-G_(n) in which one or more —CH₂—residues in said alkylene may be replaced by —S—, —SO—, SO₂—, —O—, —NH—,—N(alkyl)-, —N(phenyl)-, —N(alkylphenyl)-, —N⁺(alkyl)₂-, —N⁺(phenyl)₂-,—N⁺(alkylphenyl)₂-, —C(═O)—, —C(═S), CH═CH—, —C═C—, phenylene or—N[(C═O)alkyleneCOOH]-; G is chosen from —SO₃H, —PO₃H₂, —O—PO₃H₂, —COOH,—C(N═H)NH₂, a polyol, a sugar, a glucuronide, a sugar carbamate,—N⁺R^(6a)R^(7a)R^(8a)X⁻, and a mono or bicyclic trialkylammoniumalkylresidue; R^(6a) is C₁ to C₂₀ hydrocarbon; R^(7a) is alkyl; R^(8a) isalkyl; n is one, two, three, four or five and X is an anion.

In compounds of formula IV, R^(1c) and R^(2c) represent one or tworesidues chosen independently from H, halogen, —OH, loweralkyl, OCH₃,OCF₂H, OCF₃, CH₃, CF₂H, CH₂F, —O-loweralkyl, methylenedioxy,hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl, amino, alkylamino,dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido,alkylsulfoxide, acylamino, amidino, hydroxyamidino, guanidino,dialkylguanidino, phenyl, benzyl, phenoxy, benzyloxy, a glucuronide, anda sugar carbamate. R³ is chosen from H, —OH, fluoro, —O-loweralkyl and—O-acyl. R^(4c) represents one, two, three or four residues chosenindependently from H, halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy, a glucuronide and a sugar carbamate; andR^(5f) represents one, two, three, four or five residues chosenindependently from halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy, a sugar, a glucuronide a sugar carbamate and—N⁺R⁶R⁷R⁸X⁻.

In compounds of formula V, R^(1a), R^(2a) and R^(4a) each represents oneor two residues chosen independently from H, halogen, —OH, loweralkyl,OCH₃, OCF₂H, OCF₃, CH₃, CF₂H, CH₂F, —O-loweralkyl, methylenedioxy,hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl, amino, alkylamino,dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonyl, arylsulfonyl, acyl, carboxy, carboalkoxy, carboxamido,alkylsulfoxide, acylamino, amidino, phenyl, benzyl, phenoxy, benzyloxy.R³ is chosen from H, —OH, fluoro, —O-loweralkyl and —O-acyl. R^(5c) is-Q-A-N⁺R⁹R¹⁰R¹¹X⁻; Q is chosen from a direct bond, —O—, —S—, —NH—,—CH₂O—, —CH₂NH—, —C(═O)—, —CONH—, —NHCO—, —CH₂NH(C═O)—, —O(C═O)—,—(C═O)O—, —NHCONH—, —OCONH— and —NHCOO—; and A is chosen from C₂ to C₂₀hydrocarbon, substituted alkyl of 2 to 20 carbons, substituted aryl,substituted arylalkyl, and oxaalkyl of four to fifty carbons; and, whenQ is a direct bond, —C(═O) or —O(C═O)—, A may additionally be methylene.

In compounds of formula VI, R^(2b) represents one or two residues chosenindependently from H, halogen, —OH, loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃,CF₂H, CH₂F, —O-loweralkyl, methylenedioxy, hydroxyloweralkyl, —CN, CF₃,nitro, —S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,acyl, carboxy, carboalkoxy, carboxamido, alkylsulfoxide, acylamino,amidino, phenyl, benzyl, phenoxy, benzyloxy. R³ is chosen from H, —OH,fluoro, —O-loweralkyl and —O-acyl. One of R^(1d), R^(4d) and R^(5d) isR^(12a) and the other two of R^(1d), R^(4d) and R^(5d) are chosenindependently from hydrogen, halogen, —OH, loweralkyl, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy and R^(12a);

or, when R^(5d) is R^(12a), R^(12a), may additionally be (C₀ toC₃₀)alkylene-G_(n) in which one or more —CH₂— residues in said alkylenemay be replaced by —S—, —SO—, SO₂—, —O—, —NH—, —N(alkyl)-, —N(phenyl)-,—N(alkylphenyl)-, —N⁺(alkyl)₂-, —N⁺(phenyl)₂-, —N⁺(alkylphenyl)₂-,—C(═O)—, —C(═S), CH═CH—, —C═C—, phenylene or —N[(C═O)alkyleneCOOH]-; Gis chosen from —SO₃H, —PO₃H₂, —O—PO₃H₂, —COOH, —C(N═H)NH₂, a polyol, asugar, a glucuronide, a sugar carbamate, —N⁺R^(6a)R^(7a)R^(8a)X⁻, and amono or bicyclic trialkylammoniumalkyl residue; R¹³ is chosen from adirect bond, —C═C—, —OCH₂, —C(═O)— and —CHOH—; R¹⁴ is chosen from —OHand —OC(═O)alkyl; R¹⁵ is chosen from —CH₂OH, —CH₂C(═O)alkyl and—COOalkyl; j is 1-5; k is zero or 1-5; and n is 1-5.

In compounds of formula VII, R^(1e), R^(2a) and R^(4e) each representsone or two residues chosen independently from H, halogen, —OH,loweralkyl, OCH₃, OCF₂H, OCF₃, CH₃, CF₂H, CH₂F, —O-loweralkyl,methylenedioxy, hydroxyloweralkyl, —CN, CF₃, nitro, —S-loweralkyl,amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy,carboalkoxy, carboxamido, alkylsulfoxide, acylamino, amidino, phenyl,benzyl, phenoxy, benzyloxy. R³ is chosen from H, —OH, fluoro,—O-loweralkyl and —O-acyl. R^(5e) is chosen from

and (C₀ to C₃₀)alkylene-G_(n) in which one or more —CH₂-residues in saidalkylene may be replaced by —S—, —SO—, SO₂—, —O—, —NH—, —N(alkyl)-,—N(phenyl)-, —N(alkylphenyl)-, —N⁺(alkyl)₂-, —N⁺(phenyl)₂-,—N⁺(alkylphenyl)₂-, —C(═O)—, —C(═S), CH═CH—, —C═C—, phenylene or—N[(C═O)alkyleneCOOH]-.

In a second aspect the invention relates to pharmaceutical formulationscomprising a pharmaceutically acceptable carrier and a compound of theinvention having a pharmaceutically acceptable counter anion and,optionally additionally comprising one or more of (1) an inhibitor ofcholesterol biosynthesis; (2) a cholesterol ester transfer protein(CETP) inhibitor; (3) a bile acid sequestrant; (4) a nicotinic acid orderivative thereof, (5) a peroxisome proliferator-activator receptoralpha agonist; (6) an acylcoenzyme A:cholesterol acyltransferase (ACAT)inhibitor; (7) an obesity control medication; (8) a hypoglycemic agent;(9) an antioxidant and (10) an antihypertensive compound.

In a third aspect, the invention relates to methods for preventingand/or treating a disorder of lipid metabolism, includinghyperlipidemia, sitosterolemia and arteriosclerotic symptoms; inhibitingthe absorption of cholesterol from the intestine; reducing the bloodplasma or serum concentrations of LDL cholesterol; reducing theconcentrations of cholesterol and cholesterol ester in the blood plasmaor serum; reducing blood plasma or serum concentrations of C-reactiveprotein (CRP), reducing blood plasma or serum concentrations oftriglycerides; reducing blood plasma or serum concentrations ofapolipoprotein B; increasing blood plasma or serum concentrations ofhigh density lipoprotein (HDL) cholesterol; increasing the fecalexcretion of cholesterol; treating a clinical condition for which acholesterol absorption inhibitor is indicated; reducing the incidence ofcardiovascular disease-related events; reducing plasma or tissueconcentration of at least one non-cholesterol sterol or 5α-stanol;treating or preventing vascular inflammation; preventing, treating, orameliorating symptoms of Alzheimer's Disease; regulating the productionor level of at least one amyloid β peptide in the bloodstream and/orbrain of a subject; regulating the amount of ApoE isoform 4 in thebloodstream and/or brain; preventing and/or treating obesity; andpreventing or decreasing the incidence of xanthomas. The methodscomprise administering a compound described herein.

In a fourth aspect, the invention relates to methods and compositionsfor prevention or treatment of a cholesterol-associated tumor. Themethods comprise administering a therapeutically effective amount of acompound of the invention to a patient at risk of developing acholesterol-associated tumor or already exhibiting acholesterol-associated tumor. The method also includes coadministering atherapeutically effective amount of a compound of the invention and atleast one other anticancer agent.

In a fifth aspect, the invention relates to an article of manufacturecomprising a container, instructions, and a pharmaceutical formulationas described above. The instructions are for the administration of thepharmaceutical formulation for a purpose chosen from: the prevention ortreatment of a disorder of lipid metabolism; inhibiting the absorptionof cholesterol from the intestine; reducing the plasma or tissueconcentration of at least one non-cholesterol sterol or 5α-stanol;reducing the blood plasma or serum concentrations of LDL cholesterol;reducing the concentrations of cholesterol and cholesterol ester in theblood plasma or serum; increasing the fecal excretion of cholesterol;reducing the incidence of cardiovascular disease-related events;reducing blood plasma or serum concentrations of C-reactive protein(CRP); treating or preventing vascular inflammation; reducing bloodplasma or serum concentrations of triglycerides; increasing blood plasmaor serum concentrations of HDL cholesterol; reducing blood plasma orserum concentrations of apolipoprotein B; preventing, treating, orameliorating symptoms of Alzheimer's Disease; regulating the productionof amyloid β peptide; regulating the amount of ApoE isoform 4 in thebloodstream and/or brain; preventing and/or treating obesity; preventingor decreasing the incidence of xanthomas; and preventing or treating acholesterol-associated tumor.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the genus represented by formulae Φ, Ψ, and I-VII above areinhibitors of cholesterol absorption from the intestine. As such theyhave utility in treating and preventing lipid disorders, such ashypercholesterolemia and hyperlipidemia. Because of their effect inlowering serum lipids, the compounds are useful in the treatment andprevention of atherosclerosis. The compounds can be used advantageouslyin combination with other hypolipidemic agents, including inhibitors ofcholesterol biosynthesis, such as HMG-CoA reductase inhibitors. HMG-CoAreductase inhibitors include the “statins”: lovastatin, simvastatin,pravastatin, rosuvastatin, mevastatin, atorvastatin, cerivastatin,pitavastatin, fluvastatin, bervastatin, crilvastatin, carvastatin,rivastatin, sirrivastatin, glenvastatin and dalvastatin. A furtherlisting of non-limiting examples of antihyperlipidemic agents that maybe used in combination with the compounds of the present invention maybe found in columns 5-6 of U.S. Pat. No. 6,498,156, and in PCT WO04/004778, the disclosures of which are incorporated herein byreference. As described above, the formulation may additionally containat least one bile acid sequestrant. Sequestrants include cholestyramine,colestipol and colesevelam hydrochloride. The formulation may alsocontain a nicotinic acid or derivative thereof. Nicotinic acidderivatives include niceritrol, nicofuranose and acipimox. Theformulation may also contain a peroxisome proliferator-activatorreceptor alpha agonist, which may be a fibric acid derivative. Fibricacids include fenofibrate, clofibrate, gemfibrozil, ciprofibrate,bezafibrate, clinofibrate, binifibrate and lifibrol. The formulation mayalso contain a CETP inhibitor. Examples of such are the compoundsidentified as JTT-705 in Nature. 406, (6792):203-7 (2000) and CP-529,414(torcetrapib), described in US20030186952 and WO2000017164. Examples ofCETP inhibitors are also found in Current Opinion in InvestigationalDrugs. 4(3):291-297 (2003). The formulation may also contain an ACATinhibitor. Examples of such are the compounds identified as avasimibe inCurrent Opinion in Investigational Drugs. 3(9):291-297 (2003), andCL-277,082 in Clin Pharmacol Ther. 48(2):189-94 (1990). The formulationmay also contain an obesity control medication. Examples of obesitycontrol medications include gut hormone fragment peptide YY₃₋₃₆(PYY₃₋₃₆)(N. Engl. J. Med. 349:941, 2003; IKPEAPGE DASPEELNRY YASLRHYLNLVTRQRY) or a variant thereof, glp-1 (glucagon-like peptide-1), exendin-4(an inhibitor of glp-1), sibutramine, phentermine, phendimetrazine,benzphetamine hydrochloride (Didrex), orlistat (Xenical), diethylpropionhydrochloride (Tenuate), fluoxetine (Prozac), bupropion, ephedra,chromium, garcinia cambogia, benzocaine, bladderwrack (focusvesiculosus), chitosan, nomame herba, galega (Goat's Rue, French Lilac),conjugated linoleic acid, L-camitine, fiber (psyllium, plantago, guarfiber), caffeine, dehydroepiandrosterone, germander (teucriumchamaedrys), B-hydroxy-β-methylbutyrate, ATL-962 (Alizyme PLC), T71(Tularik, Inc.; Boulder Colo.), a ghrelin antagonist, Acomplia(rimonabant), AOD9604, alpha-lipoic acid (alpha-LA), and pyruvate. Theformulation may also contain a hypoglycemic agent. Examples of classesof hypoglycemic agents include the peroxisome proliferator-activatorreceptor gamma agonists (including, e.g. rosiglitazone, pioglitazone,ciglitazone; and metformin, phenformin, carbutamide, tolbutamide,acetohexamide, tolazamide, chlorpropamide, glyburide [glibenclamide],glipizide, and gliclazide). The formulation may also contain anantioxidant. Examples of antioxidants include probucol and AGI-1067.

The formulation may also contain an antihypertensive compound. Examplesof classes of antihypertensive compounds include thiazide derivatives,β-adrenergic blockers, calcium-channel blockers,angiotensin-converting-enzyme (ACE) inhibitor, and angiotensin IIreceptor antagonists. Examples of thiazide derivatives includehydrochlorothiazide, chlorothiazide, and polythiazide. Examples ofβ-adrenergic blockers include atenolol, metoprolol, propranolol,timolol, carvedilol, nadolol, and bisoprolol. Examples ofcalcium-channel blockers include isradipine, verapamil, nitrendipine,amlodipine, nifedipine, nicardipine, isradipine, felodipine,nisoldipine, and diltiazem. Examples of angiotensin-converting-enzyme(ACE) inhibitors include delapril, captopril, enalopril, lisinopril,quinapril, perindopril, benazepril, trandolapril, fosinopril, ramipril,and ceranapril. Examples of angiotensin II receptor antagonists includecandesartan, irbesartan, olmesartan, telmisartan, and aprosartan.

In one embodiment, the invention comprises a compound of the inventiontogether with a statin. In another embodiment, the invention furthercomprises an agent chosen from niacin, a sequestrant and a fibrate. Inanother embodiment, the invention comprises a compound of the inventiontogether with a statin, niacin, a sequestrant and a fibrate.

The present invention is also directed to methods of prevention ortreatment of a cholesterol-associated tumor in patients who are eitherat risk of developing a cholesterol-associated tumor or already exhibita cholesterol-associated tumor. The tumor may be either a benign or amalignant tumor of the prostate, breast, endometrium or colon. Thecompounds of the invention may be co-administered with at least oneother anticancer agent, which may be a steroidal antiandrogen, anon-steroidal antiandrogen, an estrogen, diethylstilbestrol, aconjugated estrogen, a selective estrogen receptor modulator (SERM), ataxane, or an LHRH analog. Tests showing the efficacy of the therapy andthe rationale for combination therapy are presented in PCT applicationWO 2004/010948, the disclosure of which is incorporated herein byreference.

The compounds of the invention may reduce both cholesterol levels invivo and epoxycholesterol formation and thereby inhibit initiation andprogression of benign and malignant cholesterol-associated tumors orcholesterol-associated cell growth or cell-masses. Compositionsdisclosed herein, for example, are useful for the treatment and/orprevention of benign prostatic hypertrophy, as well as tumors associatedwith prostate, colon, endometrial, or breast tissues.

Compositions of the invention comprise an effective dose or apharmaceutically effective amount or a therapeutically effective amountof a compound described above and may additionally comprise at least oneother anticancer agent, for the treatment or prevention of benignprostatic hypertrophy or other cholesterol-related benign or malignanttumors, particularly those associated with prostate, breast, endometrialor colon tissues. Examples of agents for use in compositions and methodsof the invention include steroidal or non steroidal antiandrogens suchas finasteride (PROSCAR®), cyproterone acetate (CPA), flutamide(4′-nitro-3′-trifluorormethyl isobutyranilide), bicalutamide (CASODEX®),and nilutamide; estrogens, diethylstilbestrol (DES); conjugatedestrogens (e.g., PREMARIN®); selective estrogen receptor modulator(SERM) compounds such as tamoxifen, raloxifene, droloxifene, idoxifene;taxanes such as paclitaxel (TAXOL®) and docetaxel (TAXOTERE®); and LHRHanalogs such as goserelin acetate (ZOLADEX®), and leuprolide acetate(LUPRON®).

Methods of the invention parallel the compositions and formulations. Themethods comprise co-administering to a patient in need of treatment atherapeutically effective amount of an azetidinone according to theinvention and one or more of: (a) a steroidal or non steroidalantiandrogen; (b) an estrogen; (c) diethylstilbestrol (DES); (d) aconjugated estrogen; (e) a selective estrogen receptor modulator (SERM);(f) a taxane; and (g) an LHRH analog. The term “selective estrogenreceptor modulator” includes both estrogen agonist and estrogenantagonists and refers to compounds that bind with the estrogenreceptor, inhibit bone turnover and prevent bone loss. In particular,estrogen agonists are compounds capable of binding to the estrogenreceptor sites in mammalian tissue and mimicking the actions of estrogenin that tissue. Estrogen antagonists are compounds capable of binding tothe estrogen receptor sites in mammalian tissue and blocking the actionsof estrogen in that tissue. Exemplary SERMs are: tamoxifen (U.S. Pat.No. 4,536,516); 4-hydroxytamoxifen (U.S. Pat. No. 4,623,660); raloxifene(U.S. Pat. No. 4,418,068); idoxifene (U.S. Pat. No. 4,839,155; anddroloxifene. For the taxanes see U.S. Pat. Nos. 6,395,770; 6,380,405;and 6,239,167. Azetidinones of the invention may also be combined with asteroidal or non steroidal antiandrogen, as described above.

Certain compounds of the invention may have the additional advantagethat they suppress serum cholesterol and/or LDL levels while themselvesnot being appreciably absorbed into the mammalian circulation upon oraladministration. As a result of the low-to-insignificant serum levels,fewer side-effects, such as drug-drug interactions, are observed.

Subgenera according to the invention include compounds of formulae Φ andΨ in which U is chosen from —CH₂CH₂CH(OH)—, —SCH₂CH₂—, —S(O)CH₂CH₂—,—SCH₂C(═O)—, —SCH₂CH(OH)—, —CH(OH)CH₂CH₂— and —(CH₂)₄—, wherein the leftend of the string is the point of attachment to the azetidinone ring andthe right end of the string is the point of attachment to the phenylring. Other subgenera of compounds of formulae Φ and Ψ include ΦA and ΨA

-   -   ΦA ΨA

Further subgenera include compounds of formulae ΦA and ΨA in which thering bearing R⁵ is in the para position, e.g.:

In another subgenus R¹ may be H or 4-fluoro; R² may be 4-fluoro; and R⁴may be H or hydroxy. In another subgenus, R⁴ and R⁵ are both hydroxy.

Other subgenera according to the invention include compounds in whichR¹, R^(1a), R², R^(2a), R⁴ and R^(4a) are chosen independently from H,halogen, —OH, and methoxy; compounds in which R¹, R², R⁴ and R⁵ arechosen from H, a sugar, a glucuronide and a sugar carbamate; compoundsin which R³ is chosen from hydrogen and hydroxy; compounds in which R⁴or R^(4a) is hydrogen; compounds in which R⁵ or R^(5a) is chosen fromhalogen, hydroxy, loweralkyl, —O-loweralkyl, CF₃, alkylsulfonyl andarylsulfonyl. Examples of compounds of formula II include those in whichone of R^(1a), R^(4a) and R^(5a) is -Q-A-N⁺R⁹R¹⁰R¹¹X⁻ and -Q-A- ischosen from (C₂ to C₂₀ hydrocarbon), —O—(C₂ to C₂₀ hydrocarbon), —NH(C₂to C₂₀ hydrocarbon), —NHCO(C₂ to C₂₀ hydrocarbon) and oxaalkyl of fourto twenty carbons. In this series of compounds, R⁹, R¹⁰ and R¹¹ are (1)loweralkyl or benzyl, or (2) R⁹, R¹⁰ and R¹¹ taken together form adiazabicyclooctane quat:

or (3) R⁹, R¹⁰ and R¹¹ taken together form a quinuclidinium quat:

Some of the compounds of the invention are quaternary salts, i.e.cationic species. Therefore they will always be presented as salts.Other compounds of formula I may contain basic or acidic residues,allowing them to be presented as salts. In the claims, reference to theacid includes its salts. Thus, for example, a claim to4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonicacid is intended to encompass as well sodium4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate.The term “pharmaceutically acceptable salt” refers to salts whosecounter ion derives from pharmaceutically acceptable non-toxic acids andbases. When the compounds contain a quat or a basic residue, suitablepharmaceutically acceptable base addition salts for the compounds of thepresent invention include inorganic acids, organic acids and, in thecase of quats, water (which formally furnishes the hydroxide anion).Examples include hydroxide, acetate, benzenesulfonate (besylate),benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate,ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide,chloride, isethionate, lactate, maleate, malate, mandelate,methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate,succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate,acetamidobenzoate, adipate, alginate, aminosalicylate,anhydromethylenecitrate, ascorbate, aspartate, calcium edetate,camphorate, camsylate, caprate, caproate, caprylate, cinnamate,cyclamate, dichloroacetate, edetate (EDTA), edisylate, embonate,estolate, esylate, fluoride, formate, gentisate, gluceptate,glucuronate, glycerophosphate, glycolate, glycollylarsanilate,hexylresorcinate, hippurate, hydroxynaphthoate, iodide, lactobionate,malonate, mesylate, napadisylate, napsylate, nicotinate, oleate,orotate, oxalate, oxoglutarate, palmitate, pectinate, pectinate polymer,phenylethylbarbiturate, picrate, pidolate, propionate, rhodanide,salicylate, sebacate, stearate, tannate, theoclate, tosylate, and thelike. When the compounds contain an acidic residue, suitablepharmaceutically acceptable base addition salts for the compounds of thepresent invention include ammonium, metallic salts made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc or organic saltsmade from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. Other base addition salts includes those made from: arecoline,arginine, barium, benethamine, benzathine, betaine, bismuth, clemizole,copper, deanol, diethylamine, diethylaminoethanol, epolamine,ethylenediamine, ferric, ferrous, glucamine, glucosamine, histidine,hydrabamine, imidazole, isopropylamine, manganic, manganous,methylglucamine, morpholine, morpholineethanol, n-ethylmorpholine,n-ethylpiperidine, piperazine, piperidine, polyamine resins, purines,theobromine, triethylamine, trimethylamine, tripropylamine, trolamine,and tromethamine.

In certain subgenera of compounds of formulae III, VI and VII, R^(1b) isR¹²; R^(2b) and R^(4b) are chosen from H, halogen, —OH, and methoxy; R¹²is (C₆ to C₂₀)alkylene-G in which one or more —CH₂— residues in saidalkylene may be replaced by —O—, —NH—, —N(alkyl)-, —C(═O)— or —CH═CH—;and G is chosen from —SO₃H, a polyol, and a sugar. In a furtherembodiment, R⁵ is R¹²; R¹, R² and R⁴ are chosen from H, halogen, —OH,and methoxy; R¹² is (C₆ to C₂₀)alkylene-G in which one or more —CH₂—residues in said alkylene may be replaced by —O—, —NH—, —N(alkyl)-,—C(═O)— or —CH═CH—; and G is chosen from —SO₃H, a polyol, and a sugar.

DEFINITIONS

Throughout this specification the terms and substituents retain theirdefinitions.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. When not otherwise restricted, theterm refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkylgroups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyland the like. Methyl is preferred. Preferred alkyl and alkylene groupsare those of C₂₀ or below (e.g. C₁, C₂, C₃, C₄, C₅, C₆, C₇, CS, C₉, C₁₀,C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀). Cycloalkyl is asubset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7,and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl,c-butyl, c-pentyl, norbornyl, adamantyl and the like.

C₁ to C₂₀ Hydrocarbon (e.g. C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀,C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀) includes alkyl,cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examplesinclude benzyl, phenethyl, cyclohexylmethyl, camphoryl andnaphthylethyl. The term “phenylene” refers to ortho, meta or pararesidues of the formulae:

Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbonatoms of a straight, branched, cyclic configuration and combinationsthereof attached to the parent structure through an oxygen. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like. Lower-alkoxy refers to groups containing oneto four carbons. Methoxy is preferred.

Oxaalkyl refers to alkyl residues in which one or more carbons (andtheir associated hydrogens) have been replaced by oxygen. Examplesinclude methoxypropoxy, 3,6,9-trioxadecyl and the like. The termoxaalkyl is intended as it is understood in the art [see Naming andIndexing of Chemical Substances for Chemical Abstracts, published by theAmerican Chemical Society, ¶196, but without the restriction of¶127(a)], i.e. it refers to compounds in which the oxygen is bonded viaa single bond to its adjacent atoms (forming ether bonds). Similarly,thiaalkyl and azaalkyl refer to alkyl residues in which one or morecarbons have been replaced by sulfur or nitrogen, respectively. Examplesinclude ethylaminoethyl and methylthiopropyl.

Polyol refers to a compound or residue having a plurality of —OH groups.Polyols may be thought of as alkyls in which a plurality of C—H bondshave been replaced by C—OH bonds. Common polyol compounds include forexample glycerol, erythritol, sorbitol, xylitol, mannitol and inositol.Linear polyol residues will generally be of the empirical formula—C_(y)H_(2y+1)O_(y), and cyclic polyol residues will generally be of theformula —C_(y)H_(2y−1)O_(y). Those in which y is 3, 4, 5 and 6 arepreferred. Cyclic polyols also include reduced sugars, such as glucitol.

Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbonatoms of a straight, branched, cyclic configuration, saturated,unsaturated and aromatic and combinations thereof, attached to theparent structure through a carbonyl functionality. One or more carbonsin the acyl residue may be replaced by nitrogen, oxygen or sulfur aslong as the point of attachment to the parent remains at the carbonyl.Examples include acetyl, propionyl, isobutyryl, t-butoxycarbonyl,benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groupscontaining one to four carbons.

Aryl and heteroaryl refer to aromatic or heteroaromatic rings,respectively, as substituents. Heteroaryl contains one, two or threeheteroatoms selected from O, N, or S. Both refer to monocyclic 5- or6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-memberedaromatic or heteroaromatic rings and tricyclic 13- or 14-memberedaromatic or heteroaromatic rings. Aromatic 6, 7, 8, 9, 10, 11, 12, 13and 14-membered carbocyclic rings include, e.g., benzene, naphthalene,indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-memberedaromatic heterocyclic rings include, e.g., imidazole, pyridine, indole,thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline,isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl, phenethyl and the like.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy,carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido(also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino,alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone,acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “sugar” is used in its normal sense, as defined in Hawley'sCondensed Chemical Dictionary, 12^(th) Edition, Richard J. Lewis, Sr.;Van Nostrand Reinhold Co. N.Y. It encompasses any carbohydrate comprisedof one or two saccharose groups. The monosaccharide sugars (often calledsimple sugars) are composed of chains of 2-7 carbon atoms. One of thecarbons carries aldehydic or ketonic oxygen, which may be combined inacetal or ketal forms. The remaining carbons usually have hydrogen atomsand hydroxyl groups (or protecting groups for hydroxyl, such asacetate). Among monosaccharides which would be considered within theterm “sugars” as intended in this application, are arabinose, ribose,xylose, ribulose, xylulose, deoxyribose, galactose, glucose, mannose,fructose, sorbose, tagatose, fucose, quinovose, rhamnose,manno-heptulose and sedoheptulose. Among the disaccharides are sucrose,lactose, maltose, and cellobiose. Unless specifically modified, thegeneral term “sugar” refers to both D-sugars and L-sugars. The sugar mayalso be protected. The sugar may be attached through oxygen (as in U.S.Pat. No. 5,756,470) or through carbon (as in PCT WO 2002066464), thedisclosures of both of which are incorporated herein by reference.

Reduced C-attached sugars or C-glycosyl compounds are also encompassedby the invention. The reduced sugars (e.g. glucitol), which could beclassed either as polyols or as sugars, are also known as alditols.Alditols are polyols having the general formula HOCH2[CH(OH)]nCH2OH(formally derivable from an aldose by reduction of the carbonyl group.

The term “glucuronide” is also used in its normal sense to refer to aglycoside of glucuronic acid.

The term “sugar carbamate” refers to mono-, di- and oligosaccharides inwhich one or more hydroxyls have been derivatized as carbamates,particularly as phenyl carbamates and substituted phenyl carbamates.[See Detmers et al. Biochim Biophys. Acta 1486, 243-252 (2000), which isincorporated herein by reference.] A preferred sugar carbamate is:

Examples of quats that fall within the definition of monocyclic andbicyclic trialkylammoniumalkyl residues include:

The term “prodrug” refers to a compound that is made more active invivo. Commonly the conversion of prodrug to drug occurs by enzymaticprocesses in the liver or blood of the mammal. Many of the compounds ofthe invention may be chemically modified without absorption into thesystemic circulation, and in those cases, activation in vivo may comeabout by chemical action (as in the acid-catalyzed cleavage in thestomach) or through the intermediacy of enzymes and microflora in thegastrointestinal GI tract.

In the characterization of the variables, it is recited that R⁹ may forma five- to seven-membered ring with A or R¹⁰; that R¹⁰ may form a doublebond with A or may form a five- to seven-membered ring with R⁹; and thatR¹¹ may form a second five- to seven-membered ring. It is intended thatthese rings may exhibit various degrees of unsaturation (from fullysaturated to aromatic), may include heteroatoms and may be substitutedwith lower alkyl or alkoxy.

In the characterization of the variables, it is recited that R-groups,such as R⁵, represent one, two, three, four or five residues chosenindependently from a list of variable definitions. The structure belowillustrates the intent of that language. In this example, R⁵ representsthree residues: —CH₃, —OH and —OCH₃.

The variables are defined when introduced and retain that definitionthroughout. Thus, for example, R³ is always chosen from H, —OH, fluoro,—O-loweralkyl and —O-acyl, although, according to standard patentpractice, in dependent claims it may be restricted to a subset of thesevalues. Superscripts are added to distinguish among residues that areattached similarly and that have overlapping Markush groups. Forexample, the substituent attached to the phenyl ring at the 1-position(i.e. on the nitrogen) of the azetidinone is always labeled R¹, but canbe R¹, R^(1a), R^(1b) or R^(1c) depending on the members of the Markushgroup defining it. For simplicity, the dependent claims, when multiplydependent, may refer to R¹ etc. This is intended to modify theappropriate value of the corresponding variable R¹, R^(1a), R^(1b),R^(1c) etc. in each claim from which it depends. Thus a claim thatrecites “a compound according to any of claims 1 to 8 wherein R¹ ischosen from H, halogen, —OH and methoxy” intends to further limit, forexample, the corresponding R^(1a) substituent in claim 6, the R^(1b)substituent in claim 7 and the R^(1c) substituent in claim 8.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, and chlorine include ³H, ¹⁴C, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds that contain those radioisotopesand/or other radioisotopes of other atoms are within the scope of thisinvention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C, radioisotopesare particularly preferred for their ease in preparation anddetectability. Radiolabeled compounds of Formulas I-VIII of thisinvention and prodrugs thereof can generally be prepared by methods wellknown to those skilled in the art. Conveniently, such radiolabeledcompounds can be prepared by carrying out the procedures disclosed inthe Examples and Schemes by substituting a readily availableradiolabeled reagent for a non-radiolabeled reagent.

The terms “methods of treating or preventing” mean amelioration,prevention or relief from the symptoms and/or effects associated withlipid disorders. The term “preventing” as used herein refers toadministering a medicament beforehand to forestall or obtund an acuteepisode or, in the case of a chronic condition to diminish thelikelihood or seriousness of the condition. The person of ordinary skillin the medical art (to which the present method claims are directed)recognizes that the term “prevent” is not an absolute term. In themedical art it is understood to refer to the prophylactic administrationof a drug to substantially diminish the likelihood or seriousness of acondition, and this is the sense intended in applicants' claims. As usedherein, reference to “treatment” of a patient is intended to includeprophylaxis. Throughout this application, various references arereferred to. The disclosures of these publications in their entiretiesare hereby incorporated by reference as if written herein.

The term “mammal” is used in its dictionary sense. The term “mammal”includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats,and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits,guinea pigs, and primates, including humans.

The compounds may be use to treat or prevent vascular inflammation, asdescribed in US published application 20030119757; to prevent, treat, orameliorate symptoms of Alzheimer's Disease and to regulate theproduction or level of amyloid β peptide and ApoE isoform 4, asdescribed in U.S. Pat. No. 6,080,778 and US published application20030013699; and to prevent or decrease the incidence of xanthomas, asdescribed in US published application 20030119809. The disclosures ofall are incorporated herein by reference.

The compounds described herein contain two or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Each chiral center may be defined, in terms ofabsolute stereochemistry, as {circle around (R)}- or (S)-. The presentinvention is meant to include all such possible isomers, as well as,their racemic and optically pure forms. Optically active {circle around(R)}- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines and singlethin lines indicate disavowal of any stereochemical implication whichthe bond it represents could generate; solid and broken bold lines aregeometric descriptors indicating the relative configuration shown butdenoting racemic character; and wedge outlines and dotted or brokenlines denote enantiomerically pure compounds of indeterminate absoluteconfiguration. Thus, the formula XI is intended to encompass both of thepure enantiomers of that pair:

Means either pure R,S:

or pure S,R:

whereas

refers to a racemic mixture of R,S and S,R, i.e. having a trans relativeconfiguration on the beta lactam ring.

The term “enantiomeric excess” is well known in the art and is definedfor a resolution of ab into a+b as

${ee}_{a} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, zero being racemic and 100 beingpure, single enantiomer. A compound which in the past might have beencalled 98% optically pure is now more precisely described as 96% ee; inother words, a 90% ee reflects the presence of 95% of one enantiomer and5% of the other in the material in question.

The configuration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration; thus a carbon-carbon double bond depictedarbitrarily herein as E may be Z, E, or a mixture of the two in anyproportion.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference. Particularattention is drawn to the chapters entitled “Protection for the HydroxylGroup, Including 1,2- and 1,3-Diols” (pages 10-86).

The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonylrespectively. A comprehensive list of abbreviations utilized by organicchemists (i.e. persons of ordinary skill in the art) appears in thefirst issue of each volume of the Journal of Organic Chemistry. Thelist, which is typically presented in a table entitled “Standard List ofAbbreviations” is incorporated herein by reference.

While it may be possible for the compounds of formulae Φ, Ψ and I-VIIIto be administered as the raw chemical, it is preferable to present themas a pharmaceutical composition. According to a further aspect, thepresent invention provides a pharmaceutical composition comprising acompound of formula Φ, Ψ or I-VIII or a pharmaceutically acceptable saltor solvate thereof, together with one or more pharmaceutically carriersthereof and optionally one or more other therapeutic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound offormula Φ, Ψ and I-VIII or a pharmaceutically acceptable salt or solvatethereof (“active ingredient”) with the carrier, which constitutes one ormore accessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier”, and this expression is intended to includeone or more inert excipients, which include starches, polyols,granulating agents, microcrystalline cellulose, diluents, lubricants,binders, disintegrating agents, and the like. If desired, tablet dosagesof the disclosed compositions may be coated by standard aqueous ornonaqueous techniques, “Pharmaceutically acceptable carrier” alsoencompasses controlled release means.

Compositions of the present invention may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must, of course, be compatible withthe compound of the invention to insure the stability of theformulation.

Examples of excipients for use as the pharmaceutically acceptablecarriers and the pharmaceutically acceptable inert carriers and theaforementioned additional ingredients include, but are not limited to:

BINDERS: corn starch, potato starch, other starches, gelatin, naturaland synthetic gums such as acacia, sodium alginate, alginic acid, otheralginates, powdered tragacanth, guar gum, cellulose and its derivatives(e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulosecalcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methylcellulose, pre-gelatinized starch (e.g., STARCH 1500® and STARCH 1500LM®, sold by Colorcon, Ltd.), hydroxypropyl methyl cellulose,microcrystalline cellulose (e.g. AVICEL™, such as, AVICEL-PH-101™, -103™and -105™, sold by FMC Corporation, Marcus Hook, Pa., USA), or mixturesthereof;

FILLERS: talc, calcium carbonate (e.g., granules or powder), dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulfate (e.g.,granules or powder), microcrystalline cellulose, powdered cellulose,dextrates, kaolin, mannitol, silicic acid, sorbitol, starch,pre-gelatinized starch, or mixtures thereof;

DISINTEGRANTS: agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, clays, other algins, othercelluloses, gums, or mixtures thereof;

LUBRICANTS: calcium stearate, magnesium stearate, mineral oil, lightmineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, otherglycols, stearic acid, sodium lauryl sulfate, talc, hydrogenatedvegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesameoil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate,ethyl laurate, agar, syloid silica gel (AEROSIL 200, W.R. Grace Co.,Baltimore, Md. USA), a coagulated aerosol of synthetic silica (DegussaCo., Plano, Tex. USA), a pyrogenic silicon dioxide (CAB-O-SIL, CabotCo., Boston, Mass. USA), or mixtures thereof;

ANTI-CAKING AGENTS: calcium silicate, magnesium silicate, silicondioxide, colloidal silicon dioxide, talc, or mixtures thereof;

ANTIMICROBIAL AGENTS: benzalkonium chloride, benzethonium chloride,benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride,cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium sorbate, propylparaben, sodium benzoate, sodiumdehydroacetate, sodium propionate, sorbic acid, thimersol, thymo, ormixtures thereof; and

COATING AGENTS: sodium carboxymethyl cellulose, cellulose acetatephthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulosephthalate, methylcellulose, polyethylene glycol, polyvinyl acetatephthalate, shellac, sucrose, titanium dioxide, camuba wax,microcrystalline wax, or mixtures thereof.

The dose range for adult humans is generally from 0.005 mg to 10 g/dayorally. Tablets or other forms of presentation provided in discreteunits may conveniently contain an amount of compound of the inventionwhich is effective at such dosage or as a multiple of the same, forinstance, units containing 5 mg to 500 mg, usually around 10 mg to 200mg. The precise amount of compound administered to a patient will be theresponsibility of the attendant physician. However, the dose employedwill depend on a number of factors, including the age and sex of thepatient, the precise disorder being treated, and its severity.

Combination therapy can be achieved by administering two or more agents,each of which is formulated and administered separately, or byadministering two or more agents in a single formulation. Othercombinations are also encompassed by combination therapy. For example,two agents can be formulated together and administered in conjunctionwith a separate formulation containing a third agent. While the two ormore agents in the combination therapy can be administeredsimultaneously, they need not be. For example, administration of a firstagent (or combination of agents) can precede administration of a secondagent (or combination of agents) by minutes, hours, days, or weeks.Thus, the two or more agents can be administered within minutes of eachother or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other orwithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other orwithin 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some caseseven longer intervals are possible. While in many cases it is desirablethat the two or more agents used in a combination therapy be present inwithin the patient's body at the same time, this need not be so.Combination therapy can also include two or more administrations of oneor more of the agents used in the combination. For example, if agent Xand agent Y are used in a combination, one could administer themsequentially in any combination one or more times, e.g., in the orderX-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

In Vivo Assay of Hypolipidemic Agents using the Rat CholesterolAbsorption Model. This model is based on models described by Burnett etal (2002), Bioorg. Med. Chem. Lett. 2002 Feb. 11; 12(3):315-8 and J.Lipid Res. 1999 October; 40(10):1747-57. Female Sprague-Dawley ratsweighing 150-250 g are separated into groups of 3 and fasted overnight.The animals (4-6/group) are dosed perorally with 300 μL test compoundsin olive oil or suitable vehicle. Thirty minutes later, 3-5 microCuries³H-cholesterol per rat are delivered perorally in 300 μL olive oil.After three hours, 200 μL serum is collected, vortexed withscintillation fluid, and measured for radioactivity in a scintillationcounter. Percent inhibition is defined as 100*(1−C_(test)/C_(ctrl)),where C_(test) and C_(ctrl) refer to ³H levels in serum for the testcompound and for the vehicle only control, respectively. Percentinhibition values are reported for a fixed dose. The ED₅₀ is the dose atwhich the half-maximal effect on serum ³H levels is observed for a giventest compound.

In Vivo Assay of Hypolipidemic Agents using the Mouse CholesterolAbsorption Model. Female CD-1 mice weighing 20-30 g are separated intogroups of 3-8 and fasted overnight. The animals (3-8/group) are dosedperorally with 200 μL test compound in olive oil or suitable vehicle.Thirty minutes later, 3-5 microCuries ³H-cholesterol per mouse aredelivered perorally in 200 μL olive oil. After three hours, 100 μL serumis collected, vortexed with scintillation fluid, and measured forradioactivity in a scintillation counter. Percent inhibition and ED₅₀are defined as in the Rat Cholesterol Absorption Model above.

In Vivo Assay of Hypolipidemic Agents Using the Hyperlipidemic Hamster:Hamsters are separated into groups of six and given a controlledcholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) forseven days. Diet consumption is monitored to determine dietarycholesterol exposure in the face of test compounds. The animals aredosed with the test compound once daily beginning with the initiation ofdiet. Dosing is by oral gavage of 0.2 mL of corn oil alone (controlgroup) or solution (or suspension) of test compound in corn oil. Allanimals moribund or in poor physical condition are euthanized. Afterseven days, the animals are anesthetized by intramuscular (IM) injectionof ketamine and sacrificed by decapitation. Blood is collected intovacutainer tubes containing EDTA for plasma lipid analysis and the liverexcised for tissue lipid analysis. Lipid analysis is conducted as perpublished procedures [Schnitzer-Polokoff, R., et al, Comp. Biochem.Physiol., 99A, 4, 665-670 (1991)] and data are reported as percentreduction of lipid versus control.

In Vivo Assay of Hypolipidemic Agents using the Hamster AcuteCholesterol Absorption Model. Male Syrian Hamsters weighing 120 g areseparated into groups of 3-6 and fasted overnight. The animals(3-6/group) are dosed perorally with 200 μL test compound in olive oilor suitable vehicle. Thirty minutes later, 3-5 microCuries³H-cholesterol per hamster are delivered perorally in 200 μL olive oil.After three hours, 100-200 μL serum is collected, vortexed withscintillation fluid, and measured for radioactivity in a scintillationcounter. Percent inhibition and ED₅₀ are defined as in the RatCholesterol Absorption Model above.

The bioabsorption of the compounds herein described may be examinedusing the Caco-2 cell monolayer model of Hilgers et al. [Pharm. Res. 7,902 (1990)].

Pharmacokinetics. To study the pharmacokinetics of compounds,bioavailability studies are carried out in rats. Compounds are preparedin suitable formulations: 5% ethanol in olive oil for oraladministration and 2% DMSO: 20% cyclodextrins in H₂O for intravenousadministration. Compounds are administered intravenously via tail veininjection and orally by gavage to independent groups of CD rats (200-250g). Serum is collected at various time points and assayed for thepresence of compounds using an LC/MS/MS detection method. Samples arediluted 15-fold in 30% acetonitrile in water, then injected (35 μL) intoa 3.2 ml/min flow of 5% methanol in water onto a sample extractioncartridge (Waters Oasis HLB Direct Connect), washed for 30 seconds, thenloaded onto a reverse phase HPLC column (Thermo Electron Betasil C18Pioneer 50×2.1 mm, 5 um particle size). Samples are eluted from thereverse phase HPLC column with a gradient: (Mobile Phase A: 5 mMammonium acetate in dH₂O, Mobile Phase B: 20% methanol in acetonitrile;40% B ramping to 95% B over 4 minutes, and holding for 3 minutes, thenreturning to initial conditions to re-equilibrate the column for 1 min,all at a flow rate of 0.3 ml/min.). A Micromass Quattro Micro (WatersCorp.; Milford, Mass.) triple quadrupole mass spectrometer operated inMRM mode is used for detection. Concentrations are calculated based onstandard concentration curves of compounds. MassLynx software (Waters,Corp.; Milford, Mass.) is used to calculate the absolute concentrationof test compound in each serum sample. A concentration versus time plotis generated from the data in Microsoft Excel, Summit Software PKSolutions 2.0 or GraphPad Prism (GraphPad Software, Inc., San Diego,Calif.) to generate pharmacokinetic curves. An area under the curve(AUC_(n), n=length of experiment in minutes or hours) is calculated fromthe concentration vs. time data by the software using the trapezoidmethod for both the orally and intravenously dosed animals. OralBioavailability (F) over the length of the experiment is calculatedusing the equation:

F=(AUC_(oral)*Dose_(i.v.))/(AUC_(i.v.)*Dose_(oral))

Representative compounds of the invention were tested in the RatCholesterol Absorption model above. The compounds of the inventionexhibited inhibition as shown below in Tables 1 and 2

TABLE 1

% Example inhibition # R⁵¹ R⁵² R⁵³ R⁵⁴ R⁵⁵ at 1 mg/kg 2 OH  54¹ 3  15¹ 4OH 72 5 OMe  26¹ 7 OH 30 8 SO₂Me 53 9 OMe OMe OMe 40 10 SO₂Me  54² 11OMe OMe 28 12 OMe 70 13 CHO 70 14 CN  32³ 15 SO₂NMe₂  8 16 CH₂OH 72 17NMe₂ 43 18 CH₂OH 48 19 OH Br 66 20 O-glucuronide 59 21 CO₂H 68 22 CO₂H52 23 NO₂  54¹ 26 NHAc  76¹ 28 NH₂ 56 56 P═O(OH)₂ 59 76 O—C6- 56glucopyranose 77 O—C6-methyl 70 gluco- pyranoside 78 O—C6-glucitol 51 81OMe OMe 17 82 SMe 28 83 NMe2 38 84 CH═CH₂ 51 85 OMe CHO 15 86 NH₂ 35 87O—CH₂—CH₂—O 59 88 CH₂CO₂H 30 89 CO₂Me 45 90 Me Me 27 91 β-naphthyl 56 92CF₃ 17 93 Me 28 94 Me F 30 95 O-gluco- 57 pyranose 96 OMe OMe OMe 69 97OMe OMe 40 98 Me  7 99 CHO 38 100 OEt 54 101 OEt 41 102 OMe OH 56 103O-nPr 21 104 OH CHO 52 105 O-iPr 15 106 CO₂H OH 66 107 OMe OMe 49 108 OHOH 69 109 O-nBu 52 110 OH CO₂H 72 111 OMe F 72 112 OH F 75 113C1-glucitol 67 114 OH OH 72 115 B(OH)₂ 70 116 Cl-gluco 81 pyranose 117Cl—CH₂- 26 glucopyranose 118 SO₃H 61 119 SH 56 120 NMe₃ ⁺ 23 ¹%inhibition at 10 mg/kg ²% inhibition at 3 mg/kg ³% inhibition at 5 mg/kg

TABLE 2

Example# R⁵¹ R⁵² R⁵³ R¹

% inhibitionat 1 mg/kg 42 OH H

87 44 OH F

24 46 OH F

30 49 OH H

30 50 OH H

27 51 OH H

39 53 SO₃H H

78 57 OH H

73 59 B(OH)₂ H

70 61 P═O(OH)₂ H

 58³ 64 Cl-glucitol H

67 65 Cl-glucitol H

 60⁵ 66 Cl-glucitol H

 71⁶ 71 C6—S-glucopyranose H

65 72 C6—R-glucopyranose H

 27⁶ 73 C6—S-glucopyranose H

59 74 C6—R-glucopyranose H

67 75 C6—S-glucitol H

68 121 OH F

72 122 P═O(OH)₂ H

67 123 SO₂Me H

72 124 OH Ph

48 125 OH H

64 127 P═O(OH)₂ H

58 128 SO₃ ⁻ Na⁺

60 ⁴The asterix indicates the point of attachment to the azetidine ring.⁵% inhibition at 0.1 mg/kg ⁶% inhibition at 0.3 mg/kg ⁷the asteriskindicates the point of attachment to the azetidine ring

In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants that are inthemselves known, but are not mentioned here.

The starting materials, in the case of suitably substitutedazetidinones, may be obtained by the methods described in WO 02/50027,WO 97/16424, WO 95/26334, WO 95/08532 and WO 93/02048, the disclosuresof which are incorporated herein by reference.

Processes for obtaining the compounds of the invention are presentedbelow. Although detailed syntheses are not presented for every examplein Tables 1 and 2, the procedures below illustrate the methods. Theother compounds were made in analogous fashion to those whose synthesisis exemplified.

EXAMPLE 1 Preparation of the intermediate4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyltrifluoromethanesulfonate

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one(150.4 mg, 0.367 mmol) and 4-dimethylaminopyridine (9.4 mg, 0.077 mmol)were dissolved in methylene chloride (10.0 mL). Triethylamine (100 μL,72.6 mg, 0.717 mmol) was added via syringe followed byN-phenyltrifluoromethanesulfonimide (143.6 mg, 0.402 mmol) added as asolid. The reaction was stirred for 3.5 h at room temperature and thenpoured into water (40 mL) and extracted with 1:1 ethyl acetate-hexane(75 mL). The organic layer was washed with water (40 mL) and brine (40mL), then dried over sodium sulfate, filtered, concentrated and purifiedby chromatography (12 g silica gel, 10% to 90% ethyl acetate-hexane) toafford4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyltrifluoromethanesulfonate (190.8 mg, 96% yield) as a clear film(eventually becomes a while solid); mp 121.6° C.; R_(f) 0.38 (2:3 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, J=8.7 Hz, 2H),7.31-7.26 (m, 4H), 7.19 (dd, J=9.0, 4.6 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H),6.95 (t, J=8.7 Hz, 2H), 4.71 (t, J=6.0 Hz, 1H), 4.67 (d, J=2.3 Hz, 1H),3.10-3.04 (m, 1H), 2.08-1.86 (m, 4H) ppm; MS [M-OH] 524.5

EXAMPLE 2 Preparation of(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-4-yl)azetidin-2-one

4-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyltrifluoromethanesulfonate (162.5 mg, 0.30 mmol) andtetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.015 mmol) weredissolved in toluene (2.5 mL). 2.0 M aqueous potassium carbonate (0.3mL) and a solution of 4-hydroxyphenylboronic acid (57.9 mg, 0.42 mmol)in ethanol (1.0 mL) were added. The reaction was stirred vigorously for5 h at refluxing temperature under a nitrogen atmosphere and thendiluted with water (2.5 mL), extracted with ethyl acetate (3×10 mL),washed with brine (10 mL), dried over sodium sulfate, filtered,concentrated and purified by chromatography (12 g silica gel, 10% to100% ethyl acetate-hexane) to afford(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-4-yl)azetidin-2-one(112 mg, 77% yield) as a clear film; mp 110° C.; R_(f) 0.5 (1:1 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.5 (d, J=9.0 Hz, 2H) 7.4 (d,J=9.0 Hz, 2H) 7.3 (m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15(m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5

In the same manner was obtained:

EXAMPLE 3(3R,4S)-4-Biphenyl-4-yl-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

(3R,4S)-4-Biphenyl-4-yl-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(11.8 mg, 54% yield) as a clear film; purification by chromatography (4g silica gel, 10% to 100% ethyl acetate-hexane) and then byreverse-phase HPLC (21 mm column, 50% to 100% acetonitrile-0.1%trifluoroacetic acid in water); R_(f) 0.47 (3:2 ethyl acetate-hexane);¹H NMR (300 MHz, CD₃OD) δ 7.63 (d, J=8.3 Hz, 2H), 7.61-7.58 (m, 2H),7.45-7.39 (m, 4H), 7.35-7.28 (m, 5H), 7.02 (t, J=8.8 Hz, 2H), 7.00 (t,J=8.8 Hz, 2H), 4.63 (t, J=5.7 Hz, 1H), 3.15-3.00 (m, 1H), 2.05-1.84 (m,5H) ppm; MS [M-OH] 452.5

EXAMPLE 4(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one(110 mg, 76% yield using a reaction time of 4 h) as an off white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 107° C.; R_(f) 0.50 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.6 (d, J=8.9 Hz, 2H), 7.3 (d, J=8.9 Hz, 2H), 7.2(m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15 (m, 1H), 2.1-1.9(m, 4H) ppm; MS [M+H] 486.5

EXAMPLE 5(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-methoxybiphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-methoxybiphenyl-4-yl)azetidin-2-one(86 mg, 67% yield using a reaction time of 16 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 103° C.; R_(f) 0.75 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.4 (m, 4H), 7.3 (m, 6H), 6.9 (m, 6H), 4.75 (m,1H), 4.65 (s, 1H), 3.85 (s, 3H), 3.2 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 482.5

EXAMPLE 6(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(6-hydroxybiphenyl-3-yl)azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(6-hydroxybiphenyl-3-yl)azetidin-2-one(36 mg, 40% yield using a reaction time of 16 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 113° C.; R_(f) 0.70 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.5-6.9 (m, 16H), 4.75 (m, 1H), 4.65 (s, 1H), 3.2(m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5

EXAMPLE 7(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′-hydroxybiphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′-hydroxybiphenyl-4-yl)azetidin-2-one(74 mg, 51% yield using a reaction time of 2 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 101° C.; R_(f) 0.50 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.6 (d, J=9.0 Hz, 2H), 7.4 (d, J=9.0 Hz, 2H),7.25 (m, 6H), 6.9 (m, 6H), 6.3 (s, 1H), 4.65 (m, 2H), 3.1 (m, 1H),2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5

EXAMPLE 8(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one(80 mg, 79% yield using a reaction time of 4 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 111° C.; R_(f) 0.40 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 8.1 (d, J=9.3 Hz, 2H), 7.8 (d, J=9.3 Hz, 2H), 7.6(d, J=8.1 Hz, 2H), 7.5 (d, J=8.1 Hz, 2H), 7.3 (m, 5H), 6.9 (m, 3H), 6.3(s, 1H), 4.7 (m, 1H), 4.6 (s, 1H), 3.1 (s, 4H), 2.1-1.9 (m, 4H) ppm; MS[M-OH] 530.6

EXAMPLE 9(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′,5′-trimethoxybiphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′,5′-trimethoxybiphenyl-4-yl)azetidin-2-one(93 mg, 90% yield using a reaction time of 2 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 103° C.; R_(f) 0.4 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.6 (d, J=9.0 Hz, 2H), 7.5 (d, J=9.0 Hz, 2H), 7.3(m, 4H), 7.0 (m, 4H), 6.8 (s, 2H), 4.7 (m, 1H), 4.6 (s, 1H), 3.9 (s,9H), 3.1 (s, 1H), 2.1-1.9 (m, 4H) ppm; MS [M-OH] 542.6

EXAMPLE 10(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylsulfonyl)biphenyl-4-yl]azetidin-2-one(92 mg, 90% yield using a reaction time of 2 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 104° C.; R_(f) 0.45 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 8.2-6.8 (m, 15H), 4.7 (m, 1H), 4.65 (s, 1H), 3.2(m, 1H), 3.1 (s, 3H), 2.1-1.9 (m, 4H) ppm; MS [M-OH] 530.6

EXAMPLE 11(3R,4S)-4-(2′,3′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

(3R,4S)-4-(2′,3′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(132.0 mg, 90% yield using a reaction time of 2 h) as a white solid;purification by chromatography (12 g silica gel, 10% to 100% ethylacetate-hexane); mp 101° C.; R_(f) 0.70 (1:1 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.6 (d, J=8.5 Hz, 2H), 7.4 (d, J=8.5 Hz, 2H), 7.3(m, 5H), 7.0 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.9 (s, 3H), 3.7 (s,3H), 3.3 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M-OH] 512.6

EXAMPLE 12(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methoxybiphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methoxybiphenyl-4-yl)azetidin-2-one(36.1 mg, 77% yield) as a clear foam; purification by chromatography (12g silica gel, 5% to 95% ethyl acetate-hexane); R_(f) 0.52 (40% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, J=8.7 Hz, 2H), 7.30(m, 7H), 7.15 (dt, J=13.5, 1.5 Hz, 1H), 7.09 (t, J=2.4 Hz, 1H), 7.00 (t,J=10.4 Hz, 2H), 6.92 (m, 3H), 4.73 (t, J=6.2 Hz, 1H), 4.67 (d, J=2.1 Hz,1H), 3.86 (s, 3H), 1.95 (m, 4H); MS [M-OH] 482.5

EXAMPLE 134′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbaldehyde

4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbaldehyde(32.7 mg, 67% yield) as a clear foam; purification by chromatography (12g silica gel, 5% to 95% ethyl acetate-hexane); R_(f) 0.72 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 10.09 (s, 1H), 8.09 (d, J=1.8Hz, 1H), 7.85 (m, 2H), 7.62 (m, 3H), 7.44 (d, J=7.8 Hz, 2H), 7.27 (m,4H), 7.03 (t, J=8.6 Hz, 2H), 6.95 (t, J=8.8 Hz, 2H), 4.74 (m, 1H), 4.70(d, J=2.4 Hz, 1H), 3.14 (m, 1H), 1.97 (m, 4H) ppm; MS [M-OH] 480.5

EXAMPLE 144′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbonitrile

4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-carbonitrile(32.5 mg, 57% yield) as a clear foam; purification by chromatography (12g silica gel, 5% to 95% ethyl acetate-hexane); R_(f) 0.69 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.84 (m, 1H), 7.79 (m, 1H),7.64 (m, 1H), 7.55 (m, 3H), 7.44 (d, J=6.6 Hz, 2H), 7.28 (m, 4H), 7.02(t, J=8.9 Hz, 2H), 6.95 (t, J=8.9 Hz, 2H), 4.75 (t, J=6.2 Hz, 1H), 4.68(d, J=2.1 Hz, 1H), 3.13 (m, 1H), 2.01 (m, 4H) ppm; MS [M-OH] 477.5

EXAMPLE 154′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-N,N-dimethylbiphenyl-4-sulfonamide

4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-N,N-dimethylbiphenyl-4-sulfonamide(39.6 mg, 73% yield) as a faint yellow foam; purification bychromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); R_(f)0.50 (50% ethyl acetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d,J=5.4 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 7.25 (m, 4H), 7.02 (t, J=8.4, 9.0 Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 4.74 (t, J=5.5 Hz, 1H), 4.69 (d, J=1.8 Hz, 1H), 3.13 (m, 1H),2.75 (s, 6H), 2.01 (m, 4H) ppm; MS [M-OH] 559.7

EXAMPLE 16(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-(hydroxymethyl)biphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-(hydroxymethyl)biphenyl-4-yl)azetidin-2-one(37.3 mg, 80% yield) as a clear foam; purification by chromatography (12g silica gel, 5% to 95% ethyl acetate-hexane); R_(f) 0.43 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.59 (m, 3H), 7.49 (m, 2H),7.37 (m, 3H), 7.27 (m, 4H), 7.02 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz,2H), 4.74 (m, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.14 (m, 1H), 1.99 (m, 4H)ppm; MS [M-OH] 482.5

EXAMPLE 17(3R,4S)-4-[4′(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

(3R,4S)-4-[4′(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(35.4 mg, 79% yield) as a white foam; purification by chromatography (12g silica gel, 5% to 95% ethyl acetate-hexane); R_(f) 0.78 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.53 (m, 4H), 7.31 (m, 8H),7.02 (t, J=8.7 Hz, 2H), 6.94 (t, J=8.7 Hz, 2H), 4.73 (m, 1H), 4.64 (d,J=2.1 Hz, 1H), 3.14 (m, 1H), 3.10 (s, 6H) 1.97 (m, 4H) ppm; MS [M+H]513.6

EXAMPLE 18(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(hydroxymethyl)phenyl]azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(hydroxymethyl)phenyl]azetidin-2-one(37.2 mg, 75% yield with a 7% impurity) as a clear film; purification bychromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane); R_(f)0.43 (50% ethyl acetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.57 (m, 4H),7.44 (d, J=8.4, 2H), 7.38 (d, J=8.4, 2H), 7.27 (m, 4H), 7.02 (t, J=8.9Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.73 (m, 3H), 4.66 (d, J=2.4 Hz, 1H),3.12 (m, 1H), 1.97 (m, 4H) ppm; MS [M-OH] 482.5

EXAMPLE 19 Preparation of(3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one(19.2 mg, 0.04 mmol) was dissolved in chloroform (0.4 mL) andtetrabutylammonium tribromide (18.8 mg, 0.04 mmol) was added at roomtemperature. After 10 minutes, saturated aqueous sodium thiosulfate (2mL) was added to quench the reaction. The mixture was poured into aseperatory funnel, extracted with dichloromethane (4×10 mL), dried oversodium sulfate, filtered and concentrated.(3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-onewas purified by chromatography (12 g silica gel, 5% to 95% ethylacetate-hexane) and then by reverse-phase HPLC (21 mm column, 50% to100% acetonitrile-0.1% trifluoroacetic acid in water) to afford(3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(8.0 mg, 34% yield) as a clear foam; R_(f) 0.51 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.49 (d, J=8.7 Hz, 1H), 7.40(m, 4H), 7.29 (m, 4H), 7.02 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H),6.80 (d, J=3.3, 1H), 6.73 (dd, J=3.0, 3.0 Hz, 1H), 4.74 (t, J=6.2 Hz,2H), 4.67 (d, J=2.1 Hz, 1H), 3.14 (m, 1H) 1.99 (m, 4H) ppm; MS [M-OH]547.4

EXAMPLE 20 Preparation of4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-ylβ-L-glucopyranosiduronic acid

Step 1: Preparation of(1S)-1-(4-fluorophenyl)-3-[(3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-{[(trifluoromethyl)sulfonyl]oxy}-phenyl)azetidin-3-yl]propylacetate

4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyltrifluoromethanesulfonate (0.16 g, 0.35 mmol) was dissolved indichloromethane (2 mL). To this was added acetic anhydride (0.04 mL,0.45 mmol), triethylamine (0.08 mL, 0.60 mmol) and4-dimethylaminopyridine (18.3 mg, 0.15 mmol). The reaction was stirredat room temperature for 18 h after which time it was diluted with water(5 mL) and extracted with dichloromethane (10 mL). The aqueous layer wasre-extracted with dichloromethane (3×10 mL) and the organic fractionswere combined, dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chromatography (12 g silica gel, 5% to 95% ethylacetate-hexane) to afford(1S)-1-(4-fluorophenyl)-3-[(3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-[(trifluoromethyl)sulfonyl]oxy}-phenyl)azetidin-3-yl]propylacetate (0.20 g, 0.35 mmol, 100%) as a clear film.

Step 2: Preparation of(1S)-1-(4-fluorophenyl)-3-[(2S,3R)-1-(4-fluorophenyl)-2-(3′-hydroxybiphenyl-4-yl)-4-oxoazetidin-3-yl]propylacetate

The product of step 1 (0.20 g, 0.35 mmol) andtetrakis(triphenylphosphine)palladium(0) (20.3 mg, 0.018 mmol) weredissolved in toluene (10 mL). 2.0 M aqueous potassium carbonate (0.35mL) and a solution of 4-hydroxyphenylboronic acid (67.8 mg, 0.49 mmol)in ethanol (2.5 mL) was added. The reaction was stirred vigorously for 4h at refluxing temperature under a nitrogen atmosphere and then dilutedwith water (2.5 mL), extracted with ethyl acetate (3×10 mL), washed withbrine (10 mL), dried over sodium sulfate, filtered, concentrated andpurified by chromatography (12 g silica gel, 5% to 95% ethylacetate-hexane) to afford(1S)-1-(4-fluorophenyl)-3-[(2S,3R)-1-(4-fluorophenyl)-2-(3′-hydroxybiphenyl-4-yl)-4-oxoazetidin-3-yl]propylacetate (157 mg, 85% yield) as a clear film.

Step 3: Preparation of(1S)-1-(4-fluorophenyl)-3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-{3′-[(2,3,4-tri-O-acetyl-6-hydroperoxy-β-L-gluco-hexodialdo-1,5-pyranosyl)oxy]biphenyl-4-yl}azetidin-3-yl)propylacetate

The product of step 2 (69.4 mg, 0.132 mmol) and methyl2,3,4-tri-O-acetyl-1-O-(2,2,2-trifluoroethanimidoyl)-D-glucopyranuronate(49.0 mg, 0.110 mmol) were azeotroped with toluene (3×15 mL) and driedin vacuo for 18 h. The dried syrup was suspended in dichloromethane (1.1mL) and the reaction was cooled to −25° C. Freshly distilled (overcalcium hydride) boron trifluoride diethyl etherate was added and thereaction was maintained at −25° C. for 2 h and warmed to 10° C. overabout 3.5 h. The mixture was diluted with saturated aqueous ammoniumchloride (2 mL), extracted with ethyl acetate (3×10 mL), washed withbrine (10 mL), dried over sodium sulfate, filtered, concentrated andpurified by chromatography (12 g silica gel, 5% to 95% ethylacetate-hexane) to afford(1S)-1-(4-fluorophenyl)-3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-{3′-[(2,3,4-tri-O-acetyl-6-hydroperoxy-β-L-gluco-hexodialdo-1,5-pyranosyl)oxy]biphenyl-4-yl}azetidin-3-yl)propyl acetate (57.2 mg, 87% based on recovered startingmaterial) as a white foam.

Step 4: Preparation of4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-ylβ-L-glucopyranosiduronic acid

The product of step 3 (57.2 mg, 0.068 mmol) was dissolved in 1:1methanol-triethylamine (2.8 mL). To this solution was added water (4.25mL). The reaction progress was monitored by TLC (5% acetic acid and 15%methanol in dichloromethane) and was complete after 19 hours. Themethanol and triethylamine were evaporated in vacuo, the residue wasacidified with 1 N aqueous hydrochloric acid (1.4 mL), extracted withethyl acetate (20 mL), washed with brine (5 mL), dried over sodiumsulfate, filtered, concentrated and purified by chromatography (10 gsilica gel, 5% acetic acid and 15% methanol in dichloromethane) toafford4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-ylβ-L-glucopyranosiduronic acid (32.6 mg, 73%) as an off-white foam; R_(f)0.37 (5% acetic acid and 15% methanol in dichloromethane); ¹H NMR (300MHz, CD₃OD) δ 7.63 (d, J=7.8 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.33 (m,7H), 7.06 (m, 5H), 5.03 (m, 1H), 4.63 (t, J=5.1, 5.1 Hz, 2H), 3.94 (m,3H), 3.13 (m, 1H) 1.91 (m, 4H) ppm; MS [M−H] 660.6

EXAMPLE 21 Preparation of4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-3-carboxylicacid

4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyltrifluoromethanesulfonate (51.1 mg, 0.094 mmol) and3-carboxyphenylboronic acid (21.9 mg, 0.132 mmol) were dissolved in 1:1toluene:ethanol (2 mL). 2.0 M aqueous potassium carbonate (0.14 mL) wasadded and the solution degassed.Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 0.005 mmol) was addedand the reaction stirred vigorously for 2 h at refluxing temperatureunder a nitrogen atmosphere. The cooled reaction was diluted intodichloromethane (15 mL), water (3 mL) was added and the pH was adjustedto 3 with 5% aqueous sodium bisulfate. The layers were separated and theaqueous layer extracted with dichloromethane (2×5 mL). The combinedorganic extracts were dried over sodium sulfate, filtered, concentratedand purified by chromatography (12 g silica gel, 5% methanol indichloromethane) to afford4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-3-carboxylicacid (41.9 mg, 86% yield) as a colorless foam; R_(f) 0.15 (5% methanolin dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ?8.31 (m, 1H), 8.09 (dt,J=7.8, 1.5 Hz, 1H), 7.79-7.39 (m, 6H), 7.23-7.32 (m, 4H), 6.90-7.02 (m,4H), 4.75 (t, J=5.7 Hz, 1H), 4.69 (d, J=2.1 Hz), 3.12 (m, 1H), 2.10-1.90(m, 4H) ppm; MS [M−H] 512.5

In the same manner was obtained:

EXAMPLE 224′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-4-carboxylicacid

4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]biphenyl-4-carboxylicacid (21.0 mg, 67% yield) as a white foam; purification bychromatography (12 g silica gel, 5% methanol in dichloromethane); R_(f)0.14 (5% methanol in dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ ?8.17(d, J=8.4 Hz, 2H), 7.65 (t, J=8.1 Hz, 4H), 7.43 (d, J=8.4 Hz, 2H),7.33-7.24 (m, 4H), 7.04-6.92 (m, 4H), 4.77 (t, J=5.7 Hz, 1H), 4.70 (d,J=2.1 Hz, 1H), 3.15 (m, 1H), 1.92-2.09 (m, 4H) ppm; MS [M−H] 512.5

EXAMPLE 23 Preparation of(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one

4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyltrifluoromethanesulfonate (50.0 mg, 0.092 mmol) and 3-nitrophenylboronicacid (21.6 mg, 0.129 mmol) were dissolved in 1:1 toluene:ethanol (2 mL).2.0 M aqueous potassium carbonate (0.092 mL) was added and the solutiondegassed. Tetrakis(triphenylphosphine)palladium(0) (5.7 mg, 0.005 mmol)was added and the reaction stirred vigorously for 2 h at refluxingtemperature under a nitrogen atmosphere. The cooled reaction was dilutedinto dichloromethane (15 mL). The layers were separated and the aqueouslayer further extracted with dichloromethane (2×5 mL). The combinedextracts were dried over sodium sulfate, filtered, concentrated andpurified by chromatography (12 g silica gel, 5% to 50% ethylacetate-hexane) to afford(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one(45.0 mg, 95% yield) as a clear film; R_(f) 0.33 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ ?8.42 (m, 1H), 8.21 (ddd,J=8.1, 2.4, 1.2 Hz, 1H), 7.89 (ddd, J=7.9, 1.5, 1.2 Hz, 1H), 7.63 (d,J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33-7.22 (m, 4H), 7.04-6.92 (m,4H), 4.76 (t, J=6.0 Hz, 1H), 4.71 (d, J=2.1 Hz, 1H), 3.14 (m, 1H),1.91-2.11 (m, 4H) ppm; MS [M-OH] 497.5

In the same manner was obtained:

EXAMPLE 26N-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)acetamide

N-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)acetamide(18.8 mg, 44% yield) as a white foam; purification by chromatography (12g silica gel, 50% ethyl acetate-hexane); R_(f) 0.07 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (b, 1H), 7.72-7.19 (m,12H), 6.99 (t, J=8.7 Hz, 2H), 6.93 (t, J=9.0 Hz, 2H), 4.72 (t, J=5.7 Hz,1H), 4.65 (d, J=2.1 Hz, 1H), 3.13 (m, 1H), 2.17 (s, 3H), 2.04-1.88 (m,4H) ppm; MS [M-OH] 509.6

EXAMPLE 28(3R,4S)-4-(4′-aminobiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-aminobiphenyl-4-yl)azetidin-2-one(42.0 mg, 95% yield) as a brown film; purification by chromatography (12g silica gel, 50% ethyl acetate-hexane); R_(f) 0.32 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.1 Hz, 2H),7.39-7.23 (m, 8H), 7.00 (t, J=8.7 Hz, 2H), 6.92 (t, J=8.7 Hz, 2H), 6.74(d, J=8.4 Hz, 2H), 4.72 (t, J=5.7 Hz, 1H), 4.63 (d, J=2.4 Hz, 1H), 3.14(m, 1H), 2.11-1.91 (m, 4H) ppm; MS [M+H] 485.5

EXAMPLE 29(3R,4S)-1-(2′,3′-difluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′-difluorobiphenyl-4-yl)azetidin-2-one

(3R,4S)-1-(2′,3′-difluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′,4′-difluorobiphenyl-4-yl)azetidin-2-one(36.9 mg, 86% yield) as a clear film; purification by chromatography (12g silica gel, 5% to 50% ethyl acetate-hexane); R_(f) 0.51 (50% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.55 (dd, J=8.3, 1.5 Hz, 2H),7.41 (d, J=6.9 Hz, 2H), 7.32-7.22 (m, 4H), 7.19-7.12 (m, 3H), 7.01 (t,J=8.7 Hz, 2H), 6.95 (t, J=9.0 Hz, 2H), 4.74 (t, J=6.0 Hz, 1H), 4.68 (d,J=2.7 Hz, 1H), 3.14 (m, 1H), 2.07-1.90 (m, 4H) ppm; MS [M-OH] 488.5

EXAMPLE 311-[4-(4-{(2S,3R)-2-(3′-hydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-1-yl}phenyl)butyl]-1-azoniabicyclo[2.2.2]octanechloride.

A quaternary salt is made in the following manner.(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid and4-bromostyrene are coupled under Suzuki conditions withtetrakis(triphenylphosphine)palladium(0) and 2.0 M aqueous potassiumcarbonate in toluene-ethanol solvent. The product is reacted withchlorosulfonyl isocyanate in ethereal solvent followed by alkali aqueouswork-up to generate a β-lactam. The amide proton is exchanged for anaryl group by reaction with 4-iodophenylcarbonylallyl (generated fromthe commercially available acid by borane reduction and protected withallyl chloroformate) using trans-1,2-cyclohexanediamine and copper (I)iodide in decane-dioxane as solvent. Deprotonation of the 3-position ofthe β-lactam with a suitable base, such as lithium diisopropylamide, andsubsequent quenching with tert-butyl{[(1S)-4-iodo-1-phenylbutyl]oxy}dimethylsilane (generated from thecommercially available (S)-(−)-3-chloro-1-phenyl-1-propanol byprotection with tert-butyldimethylchlorosilane and Finkelstein reactionwith sodium iodide) provide the 3-substituted intermediate. Theallyloxycarbonate protecting group is removed with ammonium formate andtetrakis(triphenylphosphine)palladium(0) in tetrahydrofuran and theresulting alcohol converted into the bromide using carbon tetrabromideand triphenylphosphine in dichloromethane. The silyl protecting groupsare removed from the benzyl alcohol and the phenol using 48%hydrofluoric acid in acetonitrile. The resulting compound is reactedwith a tertiary amine, such as quinuclidine, purified by HPLC and passedthrough a chloride ion-exchange column to afford1-[4-(4-{(2S,3R)-2-(3′-hydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-1-yl}phenyl)butyl]-1-azoniabicyclo[2.2.2]octanechloride.

EXAMPLE 32

Illustrated in Scheme I below is the general method for the preparationof cholesterol absorption inhibitors of general formula 32. Imines 2 aremade by refluxing 4-cyanoaniline with the appropriate aldehyde inisopropanol. Condensation of imine 2 with the benzyloxazolidinonecompound 3 using titanium tetrachloride, and subsequent cyclizationusing N,O-bistrimethylacetamide and catalytic tetra-n-butylammoniumfluoride, affords the azetidinone 4. Reduction of the cyano group in 4to the amine 5 is accomplished under hydrogen atmosphere over excessRaney-Nickel in ethanol and ammonium hydroxide. Acylation with theappropriate acid chloride [Br(CH2)_(n)COCl], followed by reaction withhydrofluoric acid in acetonitrile to remove the silyl protecting groups,and subsequent reaction with taurine provides the finally product 32. Itis noted that in this scheme the taurine is for illustration and that alarge variety of functional groups can be substituted in its place.

EXAMPLE 33

Illustrated in Scheme II below is the general method for the preparationof cholesterol absorption inhibitors of general formula 33. The aldehyde7 is made by Suzuki coupling of 4-bromobenzaldehyde with3-cyanophenylboronic acid. Refluxing 4-fluoroaniline with the aldehyde 7in isopropanol makes the imine 8. Condensation of imine 8 withbenzyloxazolidinone compound 3 using titanium tetrachloride andsubsequent cyclization, using N,O-bistrimethylacetamide and catalytictetra-n-butylammonium fluoride, affords the azetidinone 9. Reduction ofthe cyano group in 9 to the amine 10 is accomplished under hydrogenatmosphere over excess Raney-Nickel in ethanol and ammonium hydroxide.Acylation with the appropriate acid chloride [Br(CH2)_(n)COCl], followedby reaction with hydrofluoric acid in acetonitrile to remove the silylprotecting groups, and reaction with taurine provides the final product11. It is noted that in this scheme the taurine is for illustration andthat a large variety of functional groups can be substituted in itsplace.

EXAMPLE 34

Illustrated in Scheme III below is the general method for thepreparation of cholesterol absorption inhibitors of general formula 34.An imine is made by condensing 4-bromobenzaldehyde with 4-cyanoaniline,followed by condensation with the benzyloxazolidinone compound 3 usingtitanium tetrachloride, and subsequent cyclization, usingN,O-bistrimethylacetamide and catalytic tetra-n-butylammonium fluoride,to afford the azetidinone 12. Hydrofluoric acid in acetonitrile is usedto remove the silyl protecting group, and coupling tobis(pinacolato)diboron using catalytic palladium affords compound 13.Suzuki coupling with intermediate 20 affords compound 14. Reduction ofthe cyano group is accomplished under hydrogen atmosphere over excessRaney-Nickel in ethanol and ammonium hydroxide, and acetate groups areremoved with triethylamine-methanol-water to provide 15. Acylation withthe appropriate acid chloride [Br(CH2)_(n)COCl] followed by reactionwith taurine provides the final product 16. It is noted that in thisscheme the taurine is for illustration and that a large variety offunctional groups can be substituted in its place.

Synthesis of Intermediate 20: 3-Allyloxyphenyl lithium is reacted withglucopyranolactone 17, followed by reductive cleavage of the hemiketalwith triethylsilane and boron trifluoride diethyl etherate to providebenzyl-protected glycoside 18. Removal of the allyl group with palladiumcatalyst and tri-n-butyltin hydride followed by hydrogenation usingpalladium on carbon under a hydrogen atmosphere provides phenylglycoside 19. Reaction with N-phenyltrifluoromethanesulfonimide providesthe triflate and peracetylation using acetic anhyride in pyridine affordintermediate 20.

EXAMPLE 35(4S)-4-Benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one

5-(4-Fluorophenyl)-5-oxopentanoic acid (10.08 g, 47.9 mmol) andtriethylamine (6.8 mL, 4.94 g, 48.8 mmol) were dissolved intetrahydrofuran (50 mL). The reaction was cooled to −5° C. (ice/brinebath), trimethylacetyl chloride (6.0 mL, 5.87 g, 48.7 mmol) was addedquickly drop-wise and the mixture was warmed to room temperature andstirred for 1.5 h. The reaction was cooled to −5° C. (ice/brine bath)again for 30 min, filtered through Celite®, washed with cold 1:1hexane-tetrahydrofuran (60 mL) and hexane (120 mL). The filtrate wasconcentrated, dissolved in N,N-dimethylformamide (16 mL) and to thismixture was added (S)-benzyl-2-oxazolidinone (8.47 g, 47.8 mmol) and4-dimethylaminopyridine (8.57 g, 70.2 mmol) as solids. The reaction wasstirred at room temperature for 20 h, poured into 1.0 N hydrochloricacid (400 mL) and extracted with ethyl acetate (2×300 mL). The organiclayer was washed with water (400 mL), quarter saturated sodiumbicarbonate solution (400 mL), brine (200 mL), dried over sodiumsulfate, filtered, and concentrated. The residue was purified bycrystallization from hot isopropyl alcohol (75 mL) with slow cooling toroom temperature over 16 h. The crystals were filtered cold and washedwith cold isopropyl alcohol (50 mL) to afford(4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one(13.87 g, 78% yield) as a white crystalline solid; mp 114.5° C.; R_(f)0.29 (1:2 ethyl acetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 8.03-7.98 (m,2H), 7.37-7.19 (m, 5H), 7.14 (t, J=8.7 Hz, 2H), 4.72-4.64 (m, 1H),4.25-4.15 (m, 2H), 3.32 (dd, J=13.3, 3.4 Hz, 1H), 3.12-3.01 (m, 4H),2.78 (dd, J=13.3, 9.6 Hz, 1H), 2.15 (quint., J=7.2 Hz, 2H) ppm

EXAMPLE 36(4S)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one

(4S)-4-Benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one(13.87 g, 37.54 mmol) was dissolved in dichloromethane (40 mL). Into aseparate flask were added borane-methyl sulfide complex (3.6 mL, ˜38mmol), 1.0M®-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborolein toluene (1.9 mL, 1.9 mmol) and dichloromethane (20 mL). This mixturewas cooled to −5° C. (ice/methanol bath) and the ketone solution wasadded drop-wise via cannula over 5 min. The reaction was stirred at −5°C. for 5.5 h and then quenched by slow addition of methanol (9 mL), 5%hydrogen peroxide solution (30 mL) and 1 M aqueous sulfuric acid (20 mL)respectively. The reaction was poured into water (500 mL) and extractedwith ethyl acetate (500 mL). The organic layer was washed with water(500 mL), 0.1 N hydrochloric acid (300 mL) and brine (300 mL), driedover sodium sulfate, filtered, and concentrated to afford(4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one,which was used in subsequent reactions without further purification;R_(f) 0.14 (1:2 ethyl acetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ7.37-7.24 (m, 5H), 7.19 (d, J=7.3 Hz, 2H), 7.02 (t, J=8.9 Hz, 2H),4.72-4.61 (m, 2H), 4.21-4.13 (m, 2H), 3.27 (dd, J=13.2, 3.0 Hz, 1H),2.99-2.94 (m, 2H), 2.74 (dd, J=13.2, 9.6 Hz, 1H), 2.27 (br s, 1H),1.88-1.66 (m, 4H) ppm; MS [M-OH]⁺ 354.0

EXAMPLE 37(4S)-4-Benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one

(4S)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one(37.54 mmol) was dissolved in N,N-dimethylformamide (40 mL) and thenimidazole (2.97 g, 43.6 mmol) and tert-butyldimethylsilyl chloride (6.12g, 40.6 mmol) were added. The reaction was stirred at room temperaturefor 19 h, poured into 0.1 N hydrochloric acid (500 mL) and extractedwith 1:1 ethyl acetate-hexane (500 mL). The organic layer was washedwith water (2×500 mL), brine (300 mL), dried over sodium sulfate,filtered, and concentrated. The residue was purified by crystallizationfrom methanol (55 mL) by heating to a light boil and cooling slowly toroom temperature over 18 h. The crystals were filtered cold and washedwith cold methanol (45 mL) to afford(4S)-4-benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one(16.04 g, 88% yield) as a white crystalline solid; mp 87.6° C.; R_(f)0.66 (1:2 ethyl acetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.18 (m,7H), 6.99 (t, J=8.7 Hz, 2H), 4.69-4.61 (m, 2H), 4.18-4.13 (m, 2H), 3.27(dd, J=13.5, 3.2 Hz, 1H), 2.96-2.89 (m, 2H), 2.73 (dd, J=13.5, 9.7 Hz,1H), 1.82-1.63 (m, 4H), 0.88 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H) ppm;MS [M-OSi(CH₃)₂C(CH₃)₃]⁺ 354.0

EXAMPLE 38 N-{(1E)-[2-(Allyloxy)-4-bromophenyl]methylene}aniline

4-Bromosalicylaldehyde (4.02 g, 20.0 mmol) [prepared from 3-bromophenolanalogous to the procedure of Casiraghi, et. al. Journal of the ChemicalSociety, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1978), 318-21] was dissolved in anhydrous N,N-dimethylformamide (13mL). Potassium carbonate (3.9 g, 28.0 mmol) was added as a solid to givea yellow suspension. Allyl bromide (2.6 mL, 3.63 g, 30.0 mmol) was addedvia syringe. The reaction stirred for 17 h at room temperature and wasthen diluted with water and extracted three times with 1:1 ethylacetate-hexane. The combined organic layers were washed with water (5×),brine, dried over sodium sulfate, filtered and concentrated to afford2-(allyloxy)-4-bromobenzaldehyde (4.83 g, 100% yield) as a yellow solidwhich was used without further purification in the next step; R_(f) 0.38(1:9 ethyl acetate-hexane); MS [M+H]⁺ 241.0

2-(Allyloxy)-4-bromobenzaldehyde (5.05 g, 20.9 mmol) was dissolved withwarming in isopropanol (18 mL). Freshly distilled aniline (1.99 g, 21.3mmol) was added with isopropanol (4 mL) and the reaction was heated to50° C. A yellow precipitate formed within 30 min and isopropanol (5 mL)was added to aid stirring. The reaction was stirred at 50° C. for 16 h,by which time proton NMR showed no aldehyde present. The reaction wascooled with stirring. The mixture was diluted with hexane (20 mL), thesolid was filtered and washed with the mother liquor, washed with hexaneand air dried to affordN-{(1E)-[2-(allyloxy)-4-bromophenyl]methylene}aniline (5.69 g, 86%yield) as a light yellow powder; ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H),8.03 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.27-7.17 (m, 4H), 7.099 (d,J=1.8 Hz, 1H), 6.06 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.43 (AB q, J=17.3,3.0 Hz, 1H), 5.33 (AB q, J=10.5, 2.8 Hz, 1H), 4.62 (ddd, J=5.2, 1.5, 1.5Hz, 2H) ppm

EXAMPLE 39(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one

2-(Allyloxy)-4-bromobenzaldehyde (2.79 g, 8.83 mmol) and(4S)-4-Benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one(3.3 g, 6.8 mmol) were combined in a 100-mL 3-neck round bottom flaskfitted with a thermometer and nitrogen inlet. Anhydrous dichloromethane(60 mL) was added to give a light yellow solution which was cooled to−30° C. Diisopropylethylamine (2.3 mL, 1.71 g, 13.2 mmol) was added viasyringe. Titanium tetrachloride (0.86 mL, 1.48 g, 7.82 mmol) was addeddropwise over 6 min at an internal temperature between −280 to −26° C.to give a reddish brown solution. The reaction stirred under nitrogenfor 3 h between −30 to −25° C. and was then cooled to −35° C. andquenched slowly with glacial acetic acid (6 mL) over 6 min. The reactionwas poured into a cold (0° C.) 7% tartaric acid solution (125 mL). Ethylacetate (200 mL) was added and the mixture was warmed to roomtemperature with stirring. A 5% sodium sulfite solution (60 mL) wasadded and the layers were separated. The aqueous layer was extractedwith ethyl acetate (2×200 mL). The combined organic layers were washedwith a saturated sodium bicarbonate solution, water and brine, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby chromatography (120 g silica gel, 1% to 90% ethyl acetate-hexane) toafford(4S)-3-[(2R,5S)-2-[(S)-[2-(allyloxy)-4-bromophenyl](anilino)methyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-4-benzyl-1,3-oxazolidin-2-one(4.54 g, 83% yield); R_(f) 0.38 (1:4 ethyl acetate-hexane); MS [M+H]⁺801.0

(4S)-3-[(2R,5S)-2-[(S)-[2-(Allyloxy)-4-bromophenyl](anilino)methyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-4-benzyl-1,3-oxazolidin-2-one(1.2 g, 1.5 mmol) was dissolved in anhydrous methyl tert-butyl ether (10mL) and stirred at room temperature under nitrogen.N,O-bistrimethylsilylacetamide (1.1 mL, 4.5 mmol) was added followed bya catalytic amount (˜5 mg) of tetrabutylammonium fluoride trihydrate.The reaction was stirred at room temperature for 19 h, quenched at roomtemperature with glacial acetic acid (160 μL) and partitioned betweenethyl acetate and water and separated. The aqueous layer was extractedwith ethyl acetate. The combined organic layers were washed with asaturated sodium bicarbonate solution, water, brine, dried over sodiumsulfate, filtered and concentrated. The residue was purified bychromatography (120 g silica gel, 1% to 85% ethyl acetate-hexane) toafford(3R,4S)-4-[2-(allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(816 mg, 87% yield); R_(f) 0.56 (1:4 ethyl acetate-hexane)

(3R,4S)-4-[2-(Allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(1.34 g, 2.15 mmol) was dissolved in deoxygenated tetrahydrofuran (20mL). Morpholine (1.8 mL, 1.8 g, 20.6 mmol) was added with additionaldeoxygenated tetrahydrofuran (5 mL). The reaction was purged withnitrogen and tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19mmol) was added. The reaction was purged with nitrogen again. After 1.5h at room temperature the reaction was diluted with ethyl acetate,washed twice with 1 N hydrochloric acid, saturated sodium bicarbonatesolution, water and brine, dried over sodium sulfate and filtered. Thesolution was treated with activated charcoal, filtered, concentrated andpurified by chromatography (40 g silica gel, 6% to 80% ethylacetate-hexane) to afford(3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(1.04 g, 83% yield); R_(f) 0.38 (1:4 ethyl acetate-hexane); ¹H NMR (300MHz, CDCl₃) δ 7.28-7.18 (m, 6H), 7.09-6.92 (m, 6H), 5.91 (s, 1H), 4.93(d, J=2.3 Hz, 1H), 4.65 (t, J=5.4 Hz, 1H), 3.06 (ddd, J=4.8, 2.3, 2.3Hz, 1H), 1.98-1.77 (m, 4H), 0.86 (s, 9H), 0.006 (s, 3H), −0.16 (s, 3H)ppm; MS [M−H]⁺ 581.7

EXAMPLE 40(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one

(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(1.04 g, 1.79 mmol) was dissolved in anhydrous dichloromethane (5 mL),anhydrous N,N-dimethylformamide (5 mL) and stirred under nitrogen atroom temperature. 2,6-Lutidine (1.0 mL, 920 mg, 8.6 mmol) was addedfollowed by drop-wise addition of tert-butyldimethylsilyltrifluoromethane sulfonate (1.2 mL, 1.38 g, 5.22 mmol). The reaction wasstirred under nitrogen at room temperature for 2.25 h. 2,6-Lutidine(0.25 mL, 230 mg, 2.15 mmol) was added followed by addition oftert-butyldimethylsilyl trifluoromethane sulfonate (0.4 mL, 460 mg, 1.74mmol) and after a total of 4.5 h at room temperature the reaction wasdiluted with ethyl acetate and water and the layers were separated. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were washed with 0.5 N hydrochloric acid, saturated sodiumbicarbonate solution, water (4 times) and brine, dried over sodiumsulfate, filtered, concentrated and purified by chromatography (40 gsilica gel, 1% to 85% ethyl acetate-hexane) to afford(3R,4S)-4-(4-bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(1.23 g, 99% yield); R_(f) 0.57 (1:4 ethyl acetate-hexane); ¹H NMR (300MHz, CDCl₃) δ 7.33-7.14 (m, 6H), 7.09-6.91 (m, 6H), 4.99 (d, J=2.3 Hz,1H), 4.62 (t, J=5.6 Hz, 1H), 3.06 (ddd, J=4.9, 2.5, 2.3 Hz, 1H),1.97-1.69 (m, 4H), 1.03 (s, 9H), 0.84 (s, 9H), 0.33 (s, 3H), 0.29 (s,3H), −0.01 (s, 3H), −0.20 (s, 3H) ppm

EXAMPLE 415-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate

(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(293 mg, 0.50 mmol) was dissolved in anhydrous dichloromethane (3 mL).4-Dimethylaminopyridine (183 mg, 1.5 mmol) was added followed by aceticanhydride (280 μL, 302 mg, 3.0 mmol). After 1 h the reaction wasfiltered through a plug of silica gel and eluted with dichloromethane.The solvent was concentrated, azeotroped with toluene and purified bychromatography (40 g silica gel, 1% to 85% ethyl acetate-hexane) toafford5-bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate (245 mg, 78% yield); R_(f) 0.47 (1:4 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.38-7.16 (m, 9H), 7.14-6.94 (m, 3H), 4.69 (t,J=5.4 Hz, 1H), 4.64 (d, J=2.3 Hz, 1H), 3.06 (ddd, J=4.7, 2.3, 2.2 Hz,1H), 2.30 (s, 3H), 1.97-1.78 (m, 4H), 0.89 (s, 9H), 0.032 (s, 3H), −0.14(s, 3H) ppm; MS [M-OSi(CH₃)₂C(CH₃)₃]⁺ 493.8

EXAMPLE 42(3R,4S)-4-(3,3′-Dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Using Suzuki coupling methodology,5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate (100 mg, 0.16 mmol) was combined with 3-hydroxyphenyl boronicacid (29 mg, 0.21 mmol) with deoxygenated toluene (3 mL) anddeoxygenated ethanol (1 mL). 2.0 M aqueous potassium carbonate (0.31 mL,0.31 mmol) was added and the vessel was purged with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) was addedand the vessel purged again. The reaction was heated to 70° C. for 1.5h, cooled, diluted with water and extracted with ethyl acetate (2×). Thecombined organic layers were washed with water, brine, dried over sodiumsulfate, filtered, concentrated and purified by chromatography (40 gsilica gel, 20% to 90% ethyl acetate-hexane) to afford4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-ylacetate (70 mg, 69% yield)); R_(f) 0.34 (1:2 ethyl acetate-hexane); ¹HNMR (300 MHz, CDCl₃) δ 7.34-7.17 (m, 10H), 7.06-6.90 (m, 5H), 6.79 (ddd,J=8.1, 2.5, 0.8 Hz, 1H), 6.03 (br s, 1H), 4.67 (d, J=2.3 Hz, 1H), 4.64(t, J=5.6 Hz, 1H), 3.26 (ddd, J=4.8, 2.5, 2.4 Hz, 1H), 2.27 (s, 3H),1.94-1.73 (m, 4H), 0.84 (s, 9H), −0.02 (s, 3H), −0.19 (s, 3H) ppm; MS[M-OSi(CH₃)₂C(CH₃)₃]⁺ 508.0

4-{(2S,3R)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-ylacetate (70 mg, 0.11 mmol) was dissolved in methanol (2.45 mL). Water(0.73 mL) was added dropwise followed by triethylamine (2.2 mL) and thereaction stirred at room temperature for 1 h. Toluene (3 mL) andmethanol (5 mL) were added and the reaction was concentrated to give 69mg of crude(3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3,3′-dihydroxybiphenyl-4-yl)-1-phenylazetidin-2-onewhich was used without further purification.

(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3,3′-dihydroxybiphenyl-4-yl)-1-phenylazetidin-2-one(73 mg, 0.122 mmol) was dissolved in acetonitrile (5 mL) and transferredto a polypropylene conical vial. 48% Hydrofluoric acid (1 mL) was addeddropwise and the reaction stirred at room temperature for 1 h. Thereaction was quenched with 1 N sodium hydroxide (24 mL) and transferredto a flask containing pH 7.4 phosphate buffer (24 mL). The pH of thesolution was adjusted to 7.5-8.0 with saturated sodium bicarbonatesolution then extracted with ethyl acetate (3×). The combined organiclayers were washed with saturated sodium bicarbonate solution (2×),water, brine, dried over sodium sulfate, filtered, concentrated andpurified by chromatography (12 g silica gel, 40% to 100% ethylacetate-hexane) to afford(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(53 mg, 69% yield)); ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.13 (m, 7H),7.08-6.85 (m, 8H), 6.78 (ddd, J=8.1, 2.3, 0.9 Hz, 1H), 5.04 (d, J=2.3Hz, 1H), 4.61 (t, J=5.9 Hz, 1H), 3.07 (ddd, J=5.7, 1.8, 1.5 Hz, 1H),2.08-1.80 (m, 4H) ppm; MS [M+H]⁺ 584.0 [M−H]⁻ 582.0

EXAMPLE 43(3R,4S)-4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

Synthesized using a similar procedure as Example 39 starting from4-fluoroaniline and 3-bromobenzaldehyde. The benzylic TBDMS protectinggroup was removed using 48% hydrofluoric acid as described in Example42. Purified by chromatography (silica gel, 10% to 60% ethylacetate-hexane) to afford(3R,4S)-4-(3-bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(86 mg); ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.45 (m, 2H), 7.33-7.18 (m, 6H),7.07-6.91 (m, 4H), 4.72 (t, J=5.8 Hz, 1H), 4.57 (d, J=2.4 Hz, 1H), 3.10(ddd, J=4.8, 2.4, 2.4 Hz, 1H), 2.12 (br s, 1H), 2.06-1.86 (m, 4H) ppm;MS [M+HCO₂ ⁻]⁻ 516.0

EXAMPLE 44(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-3-yl)azetidin-2-one

(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(43 mg, 0.091 mmol) was coupled with 3-hydroxyphenyl boronic acid (18mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example42. Purified by chromatography (silica gel, 10% to 90% ethylacetate-hexane) to afford(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-3-yl)azetidin-2-one(19.7 mg, 45% yield); R_(f) 0.30 (1:1 ethyl acetate-hexane); ¹H NMR (300MHz, CDCl₃) δ 7.57-7.40 (m, 3H), 7.34-7.22 (m, 6H), 7.10 (ddd, 7.7, 1.6,0.9 Hz 1H), 7.04-6.90 (m, 5H), 6.84 (ddd, J=8.2, 2.6, 0.9 Hz, 1H), 5.10(br s, 1H), 4.72 (t, J=5.9 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.16 (ddd,J=5.0, 2.6, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.08-1.88 (m, 4H) ppm

EXAMPLE 45(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-3-yl)azetidin-2-one

(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(42 mg, 0.089 mmol) was coupled with 4-hydroxyphenyl boronic acid (18mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example42. Purified by chromatography (silica gel, 10% to 90% ethylacetate-hexane) to afford(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-3-yl)azetidin-2-one(27 mg, 63% yield); R_(f) 0.31 (1:1 ethyl acetate-hexane); ¹H NMR (300MHz, CDCl₃) δ 7.54-7.37 (m, 6H), 7.32-7.22 (m, 4H), 7.04-6.87 (m, 6H),5.24 (br s, 1H), 4.72 (t, J=6.0 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.17(ddd, J=5.3, 2.5, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.09-1.88 (m, 4H) ppm

EXAMPLE 46(3R,4S)-4-(4-Bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Synthesized using a similar procedure as Example 39 starting fromaniline and 4-bromobenzaldehyde. The benzylic TBDMS protecting group wasremoved using 48% hydrofluoric acid as described in Example 42.Purification by chromatography (40 g silica gel, 10% to 90% ethylacetate-hexane) afforded(3R,4S)-4-(4-bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(982.6 mg, 75% overall yield) as a clear film; R_(f) 0.45 (2:3 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.49 (d, J=8.3 Hz, 2H),7.31-7.19 (m, 8H), 7.07-6.98 (m, 3H), 4.70 (t, J=6.1 Hz, 1H), 4.61 (d,J=2.5 Hz, 1H), 3.04 (dt, J=7.4, 2.3 Hz, 1H), 2.24 (br s, 1H), 2.03-1.86(m, 4H) ppm

EXAMPLE 47(3R,4S)-4-(5-Bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Synthesized using the same procedure as Example 39 starting from anilineand 5-bromo-2-pyridinecarboxaldehyde (prepared using a proceduredescribed by Wang et. al., Tetrahedron Letters 41 (2000), 4335-4338).The benzylic TBDMS protecting group was removed using 48% hydrofluoricacid as described in Example 42. Purification by chromatography (12 gsilica gel, 15% to 90% ethyl acetate-hexane) afforded(3R,4S)-4-(5-bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(23.3 mg, 3% overall yield) as a clear film; R_(f) 0.07 (1:4 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d, J=2.3 Hz, 1H), 7.80(dd, J=8.3, 2.3 Hz, 1H), 7.34-7.29 (m, 3H), 7.24-7.17 (m, 4H), 7.09-6.99(m, 3H), 4.82 (d, J=2.5 Hz, 1H), 4.75-4.71 (m, 1H), 3.21 (dt, J=7.0, 2.3Hz, 1H), 2.31-1.89 (m, 5H) ppm

EXAMPLE 48(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Synthesized using the same procedure as Example 39 starting from anilineand 5-bromo-2-thiophenecarboxaldehyde. The benzylic TBDMS protectinggroup was removed using 48% hydrofluoric acid as described in Example42. Purification by chromatography (40 g silica gel, 15% to 90% ethylacetate-hexane) afforded(3R,4S)-4-(5-bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(212.4 mg, 23% overall yield) as a white solid; R_(f) 0.13 (1:4 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.21 (m, 6H), 7.10-7.06(m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.89 (dd, J=19.7, 3.8 Hz, 2H), 4.83 (d,J=2.4 Hz, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.25-3.19 (m, 1H), 2.20 (br s,1H), 2.01-1.83 (m, 4H) ppm

EXAMPLE 49(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)pyridin-2-yl]-1-phenylazetidin-2-one

(3R,4S)-4-(5-Bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(23 mg, 0.051 mmol) was coupled with 3-hydroxyphenyl boronic acid (9.2mg, 0.067 mmol) under standard Suzuki conditions illustrated by Example42. Purification by chromatography (4 g silica gel, 15% to 100% ethylacetate-hexane) afforded(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)pyridin-2-yl]-1-phenylazetidin-2-one(20.7 mg, 87% yield) as a clear film; R_(f) 0.14 (1:1 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 8.88 (d, J=2.2 Hz, 1H), 7.88(dd, J=8.2, 2.3 Hz, 1H), 7.86-7.80 (m, 1H), 7.39-7.22 (m, 7H), 7.12-7.02(m, 3H), 6.96 (t, J=8.7 Hz, 2H), 6.96-6.91 (m, 1H), 4.97 (d, J=2.3 Hz,1H), 4.76-4.72 (m, 1H), 3.28-3.22 (m, 1H), 3.20 (br s, 1H), 2.17-1.90(m, 4H), 1.80 (br s, 1H) ppm; MS [M+H]⁺ 469.0

EXAMPLE 50(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one

(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(90.2 mg, 0.196 mmol) was coupled with 3-hydroxyphenyl boronic acid(32.2 mg, 0.233 mmol) under standard Suzuki conditions illustrated byExample 42. Purification by chromatography (12 g silica gel, 15% to 100%ethyl acetate-hexane) afforded(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one(77.6 mg, 84% yield) as a clear foam; R_(f) 0.36 (1:1 ethylacetate-hexane); ¹H NMR (300 MHz, CD₃OD) δ 7.31-6.93 (m, 14H), 6.70(ddd, J=8.0, 2.3, 1.0 Hz, 1H), 4.89-4.88 (m, 1H), 4.64-4.59 (m, 1H),3.77 (br s, 2H), 3.25-3.21 (m, 1H), 1.97-1.83 (m, 4H) ppm; MS [M-OH]⁺456.0

EXAMPLE 51(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one

(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(69.8 mg, 0.152 mmol) was coupled with 4-hydroxyphenyl boronic acid(25.2 mg, 0.183 mmol) under standard Suzuki conditions illustrated byExample 42. Purification by chromatography (12 g silica gel, 15% to 100%ethyl acetate-hexane) afforded(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one(40.7 mg, 56% yield) as a clear foam; R_(f) 0.39 (1:1 ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.64-7.60 (m, 4H), 7.56-7.48(m, 5H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=8.6 Hz, 2H),6.81 (br s, 1H), 5.14 (d, J=2.3 Hz, 1H), 5.00-4.95 (m, 1H), 3.57-3.50(m, 1H), 2.29-2.11 (m, 4H) ppm; MS [M+H]⁺ 474.0

EXAMPLE 53 Sodium4′-{(2S,3R)-3-[(3S/R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonate

5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate (140.0 mg, 0.223 mmol) was dissolved in acetonitrile (8.0 mL)and 48% hydrofluoric acid (0.8 mL) into a polypropylene Falcon® tube.The reaction was stirred for 4 h at room temperature and then pouredinto 0.5 M potassium phosphate (50 mL), extracted with 1:1 ethylacetate-hexane (50 mL), washed with saturated sodium bicarbonatesolution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered,concentrated and purified by chromatography (12 g silica gel, 15% to 90%ethyl acetate-hexane) to afford5-bromo-2-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate (114.5 mg, 100% yield) as a clear foam; R_(f) 0.11 (1:4 ethylacetate-hexane).

5-Bromo-2-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate (14.5 mg, 0.223 mmol) and 3-thioanisoleboronic acid (48.3 mg,0.287 mol) were dissolved in toluene (3.0 mL) and ethanol (1.5 mL). Asolution of 2.0 M aqueous sodium carbonate (0.215 mL, 0.43 mmol) andsolid tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 0.0125 mmol)were added and the vessel was vacuum/nitrogen purged (3×). The reactionwas stirred vigorously for 4 h at 60° C. under a nitrogen atmosphere andthen poured into 0.2 N hydrochloric acid (50 mL), extracted with 1:1ethyl acetate-hexane (75 mL), washed with brine (50 mL), dried oversodium sulfate, filtered and concentrated to afford a mixture ofproducts which was used directly in the next step; R_(f) 0.79 (2:1 ethylacetate-hexane) for(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylthio)biphenyl-4-yl]-1-phenylazetidin-2-oneand 0.84 (2:1 ethyl acetate-hexane) for4-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-(methylthio)biphenyl-3-ylacetate.

A 1:1 mixture of(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylthio)biphenyl-4-yl]-1-phenylazetidin-2-oneand4-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-(methylthio)biphenyl-3-ylacetate (0.223 mmol) was dissolved in dichloromethane (10 mL) and cooledto 0° C. 3-Chloroperoxybenzoic acid (64.3 mg, 0.373 mmol) was added inportions while monitoring by LCMS to make the arylsulfoxide. Onceaddition was complete the reaction was poured into quarter saturatedsodium bicarbonate solution (50 mL), extracted with 1:1 ethylacetate-hexane (75 mL), washed brine (50 mL), dried over sodium sulfate,filtered and concentrated. The residue was dissolved in dichloromethane(10 mL) and the Pummerer rearrangement was effected by the addition oftrifluoroacetic anhydride (100 μL, 148.7 mg, 0.708 mmol). The reactionwas stirred at room temperature for 4 h and then 3-chloroperoxybenzoicacid (121.7 mg, 0.705 mmol) was added to convert to the sulfone. Themixture was stirred for 15 min at room temperature, concentrated anddissolved in 3:3:1 methanol-triethylamine-water (7 mL) to hydrolyze theacetate and trifluoroacetate groups. The reaction was stirred for 2 h atroom temperature, concentrated and dissolved in dichloromethane (10 mL).3-Chloroperoxybenzoic acid (49.2 mg, 0.285 mmol) was added to oxidizethe compound to the sulfonic acid. The reaction was stirred for 10 minat room temperature, diluted with 1:1 ethyl acetate-hexane (50 mL) andextracted with 1% saturated sodium bicarbonate solution (3×50 mL). Theaqueous layer was acidified with 1.0 N hydrochloric acid (10 mL),extracted with ethyl acetate (2×75 mL), diluted with triethylamine (1.0mL), concentrated, purified by reverse-phase HPLC (Polaris C18-A 10μ250×21.2 mm column, 25% to 100% acetonitrile-0.1% trifluoroacetic acidin water) and passed through Dowex® sodium ion exchange resin to affordsodium4′-{(2S,3R)-3-[(3S/R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonate(45.3 mg, 36% yield) as an off-white solid; ¹H NMR (300 MHz, CD₃OD) δ8.04-6.98 (m, 16H), 5.17 (d, J=2.2 Hz, 0.66H), 5.14 (d, J=2.2 Hz,0.33H), 4.70-4.60 (m, 1H), 3.21-3.14 (m, 1H), 2.09-1.89 (m, 4H) ppm; MS[M-Na]⁻ 546.0

EXAMPLE 54(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one

(3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(0.60 g, 0.86 mmol) was stirred at room temperature in dry methanol (20mL) under a nitrogen atmosphere. Potassium fluoride (0.10 g, 1.72 mmol)was added and the reaction mixture was stirred 1.5 h at roomtemperature. The solution was poured into ethyl acetate and washedsuccessively with water (2×), 10% aqueous sodium bicarbonate, water andbrine. The organic solution was dried over sodium sulfate, filtered,concentrated and purified by chromatography over silica gel using ethylacetate-hexane (gradient: 5% ethyl acetate to 50%) to afford(3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one(0.46 g, 92%) as a white foam; ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=8.2,Hz, 2H,) 7.37 (d, J=8.2 Hz, 2H), 6.9-7.4 (m, 12H), 6.8 (m, 1H), 4.9 (brs, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.63 (d, J=2.5 Hz, 1H), 3.0-3.1 (m, 1H),1.8-2.0 (m, 4H), 0.87 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H)

EXAMPLE 554′-{(2S,3R)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yltrifluoromethanesulfonate

(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one(0.46 g, 0.79 mmol) was stirred at room temperature in drydichloromethane (15 mL) under a nitrogen atmosphere.N-Phenyltrifluoromethanesulfonimide (0.39 g, 1.09 mmol), triethylamine(0.23 mL, 1.65 mmol) and 4-(dimethylamino)pyridine (0.02 g, 0.2 mmol)were added in succession and the reaction mixture was stirred 2 h atroom temperature. The solution was poured into 0.5N aqueous hydrochloricacid (20 mL) and extracted with ethyl acetate. The organic phase waswashed successively with water, 10% aqueous sodium bicarbonate, waterand brine. The organic solution was dried over sodium sulfate, filteredand the solvent was removed in vacuo to afford4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yltrifluoromethanesulfonate as a white foam (0.56 g, 100%) bychromatography over silica gel using ethyl acetate-hexane (gradient: 5%ethyl acetate to 50%) ¹H NMR (300 MHz, CDCl₃) δ 6.9-7.3 (m, 17H), 4.68(t, J=5.7 Hz, 1H), 4.65 (d, J=2.5 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m,6H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H).

EXAMPLE 56(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonicacid

This reaction was performed using a PersonalChemistry™ microwaveinstrument set at normal absorbance, fixed hold time and 30 secpre-stirring. A 10-mL reaction vial was charged with4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yltrifluoromethanesulfonate (0.27 g, 0.38 mmol), dimethyl phosphite (0.070mL, 0.76 mmol) and triethylamine (0.15 mL, 1.08 mmol) in toluene (4 mL).Nitrogen was bubbled through the stirred solution for 5 min,tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, and thesolution was covered with a blanket of nitrogen and sealed. The reactionmixture was heated for 11 min at 160° C., then cooled to roomtemperature and diluted with ethyl acetate. The yellow solution waswashed successively with 0.5 M hydrochloric acid (20 mL) water (3×) andbrine. The organic solution was dried over sodium sulfate, filtered andthe solvent was removed by rotary evaporation under reduced pressure.Pure dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonatewas obtained as a white foam (0.26 g, 65%) by chromatography over silicagel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). ¹HNMR (300 MHz, CDCl₃) δ 8.00 (dt, J=14.2, 1.5 Hz, 1H), 7.60 (d, J=8.5 Hz,2H), 7.40 (d, J=8.5 Hz, 2H), 6.9-7.8 (m, 12H), 4.68 (t, J=5.7 Hz, 1H),4.64 (d, J=2.4 Hz, 1H), 3.81 (d, J=0.9 Hz, 1H), 3.77 (d, J=0.9 Hz, 1H),3.0-3.1 (m, 1H), 1.8-2.2 (m, 4H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s,3H) ppm

A solution of dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate(0.32 g, 0.47 mmol) in dry dichloromethane (15 mL) under nitrogen wascooled in an ice bath and bromotrimethylsilane (0.30 mL, 2.27 mmol) wasdripped in over 5 min. The reaction mixture was stirred at roomtemperature for 3 h, then poured into ice water (20 mL) and extractedwith ethyl acetate. The organic solution was washed successively withwater (2×) and brine. The organic solution was dried over sodiumsulfate, filtered and the solvent was removed by rotary evaporationunder reduced pressure. The residue was purified by reverse-phase HPLC(Polaris C18-A 10μ 250×21.2 mm column, 20% to 70% acetonitrile-0.1%trifluoroacetic acid in water) to afford(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonicacid (0.25 g, 99%) as a white powder; ¹H NMR (300 MHz, CD₃OD) δ 8.04 (brd, J=14.2 Hz, 1H) 7.68 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H),7.0-7.8 (m, 12H), 4.93 (d, J=2.2 Hz, 1H), 4.63 (t, J=5.2 Hz, 1H),3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H]-531, [2M−H]-1061

EXAMPLE 57(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one

(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-onewas synthesized in a manner similar to that described in Example 42.(3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(0.60 g, 0.86 mmol) was stirred at room temperature in acetonitrile (18mL) in a 40 ml polypropylene vial fitted with a screw cap. Hydrogenfluoride (48% aqueous, 2.0 mL, 48 mmol) was dripped in and stirring wascontinued at room temperature overnight. The reaction mixture was pouredinto an aqueous solution of 1 N sodium hydroxide (45 mL) buffered with 1M sodium phosphate (45 mL, pH 7.4), then the pH of the solution wasbrought to pH 8 with the addition of aqueous 10% sodium bicarbonatesolution. The mixture was extracted with ethyl acetate and the organicsolution was washed successively with 10% sodium bicarbonate solution(2×), water (2×) and brine. The organic solution was dried over sodiumsulfate, filtered and the solvent was removed by rotary evaporationunder reduced pressure. Pure(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-onewas obtained as a white foam (0.35 g, 87%) by chromatography over silicagel using ethyl acetate-hexane (gradient: 10% ethyl acetate to 60%) ¹HNMR (300 MHz, CDCl₃) δ 7.56 (d, J=8.2, Hz, 2H), 7.39 (d, J=8.2 Hz, 2H),7.0-7.3 (m, 12H), 6.80-6.86 (m, 1H), 5.00 (br s, 1H), 4.74 (t, J=6.2 Hz,1H), 4.69 (d, J=2.2 Hz, 1H), 3.1-3.2 (m, 1H), 2.20 (br s, 1H), 1.8-2.1(m, 4H) ppm; MS [M+HCO₂ ⁻]⁻ 512

EXAMPLE 584′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yltrifluoromethanesulfonate

(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one(0.353 g, 0.77 mmol) was stirred at room temperature in drydichloromethane (15 mL) under a nitrogen atmosphere.Phenyltrifluoromethanesulfonimide (0.38 g, 1.69 mmol), triethylamine(0.23 mL, 1.65 mmol) and 4-dimethylaminopyridine (0.02 g, 0.2 mmol) wereadded in succession and the reaction mixture was stirred 1 h at roomtemperature. The solution was poured into 0.5 N hydrochloric acid (20mL) and extracted with ethyl acetate. The organic phase was washedsuccessively with water, 10% aqueous sodium bicarbonate, water andbrine. The organic solution was dried over sodium sulfate, filtered andthe solvent was removed by rotary evaporation under reduced pressure.Pure4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yltrifluoromethanesulfonate was obtained as a white foam (0.35 g, 76%) bychromatography over silica gel using ethyl acetate-hexane (gradient: 5%ethyl acetate to 50%); ¹H NMR (300 MHz, CDCl₃) δ 7.0-7.6 (m, 17H), 4.74(t, J=6.4 Hz, 1H), 4.72 (d, J=2.2 Hz, 1H), 3.1-3.2 (m, 1H), 2.16 (br s,1H), 1.9-2.1 (m, 4H) ppm; MS [M+HCO₂ ⁻]⁻ 644

EXAMPLE 59(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronicacid

4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yltrifluoromethanesulfonate (0.15 g, 0.25 mmol), bis(pinacolato)diboron(0.70 g, 0.27 mmol), potassium acetate (0.80 g, 0.81 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.020 g,0.03 mmol) were combined in dimethylsulfoxide (7 mL) in a 40-mLscrew-cap vial at room temperature. The mixture was covered with anitrogen atmosphere, the vial was sealed and the reaction was heatedovernight at 80° C. The reaction mixture was cooled to room temperature,poured into water and extracted with ethyl acetate. The organic phasewas washed successively with water (2×) and brine, dried over sodiumsulfate, filtered and the solvent was removed by r o t a r y evaporationunder reduced pressure. Pure(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl]azetidin-2-onewas obtained as a white foam (0.097 g, 67%) by chromatography oversilica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to70%) ¹H NMR (300 MHz, CDCl₃) δ 8.01 (br s, 1H), 7.75-7.85 (m, 1H),7.0-7.7 (m, 15H), 4.74 (t, J=6.2 Hz, 1H), 4.69 (d, J=2.2 Hz, 1H),3.0-3.2 (m, 1H), 1.50 (br s, 1H), 1.8-2.1 (m, 4H), 1.35 (s, 6H), 1.24(s, 6H) ppm; MS [M+HCO₂ ⁻]⁻ 577

(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl]azetidin-2-one(0.020 g, 0.034 mmol) was dissolved in ethanol (3 mL) and water (1 mL)at room temperature. Solid sodium carbonate (0.10 g, 1.2 mmol) was addedand the mixture was rapidly stirred 2 h at room temperature. Thesolution was poured into 0.5 N hydrochloric acid (4 mL) and extractedwith ethyl acetate. The organic phase was washed successively with water(2×) and brine, then dried over sodium sulfate, filtered and the solventwas removed by rotary evaporation under reduced pressure. The residuewas purified by reverse-phase HPLC (Polaris C18-A 10μ 250×21.2 mmcolumn, 40% to 75% acetonitrile-0.1% trifluoroacetic acid in water) toafford(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronicacid as a white powder (0.012 g, 70%); ¹H NMR (300 MHz, CD₃OD) δ 7.83(br s, 1H), 7.0-7.7 (m, 16H), 4.92 (d, J=2.7 Hz, 1H), 4.63 (t, J=6.2 Hz,1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M+HCO₂ ⁻]⁻ 540

EXAMPLE 60 Dimethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate

3-Chlorophenol (0.50 g, 3.89 mmol) was stirred at room temperature indry dichloromethane (20 mL) under a nitrogen atmosphere.Phenyltrifluoromethanesulfonimide (1.80 g, 5.0 mmol), triethylamine(0.90 mL, 6.4 mmol) and 4-dimethylaminopyridine (0.10 g, 0.8 mmol) wereadded in succession and the reaction mixture was stirred 2 h at roomtemperature. The solution was poured into 0.5 N hydrochloric acid (20mL) and extracted with ethyl acetate. The organic phase was washedsuccessively with water, 10% aqueous sodium bicarbonate and brine. Theorganic solution was dried over sodium sulfate, filtered and the solventwas removed by rotary evaporation under reduced pressure. Pure3-chlorophenyl trifluoromethanesulfonate was obtained as a colorless oil(0.92 g, 91%) by chromatography over silica gel using ethylacetate-hexane (gradient: 5% to 50% ethyl acetate-hexane); ¹H NMR (300MHz, CDCl₃) δ 7.16-7.50 (m) ppm

This reaction was performed using a PersonalChemistry™ microwaveinstrument set at normal absorbance, fixed hold time and 30 secpre-stirring. A 10-mL reaction vial was charged with 3-chlorophenyltrifluoromethanesulfonate (0.60 g, 2.30 mmol), dimethyl phosphite (0.42mL, 4.58 mmol) and triethylamine (0.64 mL, 4.59 mmol) in toluene (4 mL).Nitrogen was bubbled through the stirred solution for 5 min, thetetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, the solutionwas covered with a blanket of nitrogen and sealed. The reaction mixturewas heated 11 min at 160° C., then cooled to room temperature anddiluted with ethyl acetate. The yellow solution washed successively withwater (3×) and brine. The organic solution was dried over sodiumsulfate, filtered and the solvent was removed by rotary evaporationunder reduced pressure. Pure dimethyl (3-chlorophenyl)phosphonate wasobtained as a colorless oil (0.27 g, 57%) by chromatography over silicagel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). ¹HNMR (300 MHz, CDCl₃) δ 7.77 (br d, J=13.7 Hz, 1H), 7.68 (ddt, J=13.0,7.5, 1.4 Hz, 1H), 7.53 (dquint., J=8.0, 1.1 Hz, 1H), 7.38-7.45 (m, 1H),3.79 (s, 3H), 3.75 (s, 3H) ppm; MS [M+H]⁺ 221, [2M+H]⁺ 441

Bis(dibenzylidineacetone)palladium(0) (0.10 g, 0.17 mmol andtricyclohexylphosphine (0.12 g, 0.43 mmol) were stirred 30 min in drydioxane (1.0 mL) under an atmosphere of nitrogen at room temperature.Dimethyl (3-chlorophenyl)phosphonate (0.50 g, 2.26 mmol),bis(pinacolato)diboron (0.70 g, 0.27 mmol) and potassium acetate (0.30g, 0.30 mmol) were mixed in dry dioxane (3.0 mL) at room temperatureunder a nitrogen atmosphere in a separate flask. A portion of thepalladium catalyst solution (0.20 mL) was syringed into the flaskcontaining the chlorophosphonate and this mixture was heated at 80° C.Additional 0.2 mL portions of the catalyst solution were syringed intothe reaction mixture after 4 h and 8 h of heating at 80° C., thenheating was continued overnight at 80° C. The reaction mixture wasfiltered through Celite® and the solvent was removed by rotaryevaporation under reduced pressure. Chromatography over silica gel usingethyl acetate-hexane (gradient: 0% ethyl acetate to 80%) dimethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate as acolorless oil (0.41 g). ¹H NMR showed a 60:40 mixture of product plusrecovered starting material. This mixture was used as is in the nextreaction without further purification. ¹H NMR (300 MHz, CDCl₃) δ 8.22(d, J=13.2 Hz, 1H), 7.95-8.00 (m, 1H), 7.88 (ddt, J=13.0, 7.5, 1.4 Hz,1H), 7.43-7.50 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H) ppm; MS [M+H]⁺ 312,[2M+H]⁺ 625

EXAMPLE 61(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonicacid

(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(0.080 g, 0.11 mmol), crude dimethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate(0.054 g total, 0.030 g calculated, 0.096 mmol) and aqueous 2 Mpotassium carbonate (0.12 mL, 0.24 mmol) were mixed in ethanol (1.0 mL)and toluene (3.0 mL). The solution was deoxygenated by bubbling nitrogenthrough the mixture for 5 min while stirring.Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added and thereaction was heated for 3 h at 70° C. under an atmosphere of nitrogen.The reaction was cooled to room temperature, diluted with ethyl acetate,washed with water and brine, dried over sodium sulfate and concentratedby rotary evaporation under reduced pressure. The product was purifiedby chromatography over silica gel using ethyl acetate-hexane (gradient:10% ethyl acetate to 80%) to afford dimethyl(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonateas a colorless syrup (0.065 g, 84%). ¹H NMR (300 MHz, CDCl₃) δ 6.9-8.0(m, 16H), 5.09 (d, J=2.2 Hz, 1H), 4.64 (d, J=6.1 Hz, 1H), 3.79 (d, J=2.4Hz, 3H), 3.76 (d, J=2.4 Hz, 3H), 3.05-3.15 (m, 1H), 1.8-2.0 (m, 4H),1.06 (s, 9H), 0.85 (s, 9H), 0.36 (s, 3H), 0.33 (s, 3H), 0.00 (s, 3H),−0.20 (s, 3H) ppm

Dimethyl(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate(0.047 g, 0.058 mmol) was stirred at room temperature in dry methanol (2mL) under a nitrogen atmosphere. Potassium fluoride (0.02 g, 0.34 mmol)was added and the reaction mixture was stirred for 30 min at roomtemperature. The solution was poured into ethyl acetate and washedsuccessively with water (2×), and brine. The organic solution was driedover sodium sulfate, filtered and the solvent was removed by rotaryevaporation under reduced pressure. Dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonatewas obtained as a colorless glass (0.041 g, 100%) was used directly inthe next reaction without further purification; MS [M−H]⁺ 688

A solution of dimethyl(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonate(0.041 g, 0.059 mmol) in dry dichloromethane (5 mL) under nitrogen wascooled in ice and bromotrimethylsilane (0.030 mL, 0.30 mmol) was drippedin over 5 min. The reaction mixture was stirred at room temperature for3 h, then methanol (1 mL) was added and the reaction was partitionedbetween water and ethyl acetate. The organic solution was washedsuccessively with water (2×) and brine. The organic solution was driedover sodium sulfate, filtered and the solvent was removed by rotaryevaporation under reduced pressure. The residue was purified byreverse-phase HPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 59%acetonitrile-0.1% trifluoroacetic acid in water) to afford(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonicacid as a white powder (0.014 g, 44%); ¹H NMR (300 MHz, CD₃OD) δ 8.0 (d,J=13.6 Hz, 1H), 6.9-7.8 (m, 15H), 5.17 (d, J=2.1 Hz, 1H), 4.63 (d, J=5.2Hz, 1H), 3.15-3.25 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M−H]⁺ 546, [2M−H]⁺1093

EXAMPLE 62(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol

D-Glucopyranose (1.0 g, 5.55 mmol) was dissolved in 5 mL of aceticanhydride and 7 mL of pyridine at 0° C. To this mixture was added4-dimethylaminopyridine (200 mg, 1.63 mmol), and the reaction wasstirred while warming to room temperature. TLC (40% ethylacetate-hexane) after 18 h showed complete consumption of the startingmaterial and formation of a higher running spot. The reaction was pouredinto 50 mL of water and extracted into dichloromethane (3×50 mL). Theorganic layers were combine, washed with 1 N hydrochloric acid (3×20mL), dried over sodium sulfate, filtered, concentrated and purified bycolumn chromatography (50 g silica gel, 40% ethyl acetate-hexane) toafford 1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (2.10 g, 5.37 mmol).

1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (1.0 g, 2.60 mmol) wasdissolved in 20 mL of dichloromethane and 1.90 mL of hydrobromic acid(33% in acetic acid) at 0° C., and the reaction was stirred whilewarming to room temperature. TLC (40% ethyl acetate-hexane) after 18 hshowed complete consumption of the starting material and formation of ahigher running spot. The reaction was slowly diluted with saturatedsodium bicarbonate (25 mL), extracted into dichloromethane (2×100 mL),dried over sodium sulfate, filtered and concentrated to afford2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide which was used withoutpurification.

Magnesium (O) (400 mg) was suspended in 17 mL of anhydrous diethylether, and to the suspension was added 100 μL of 1,2-dibromoethane.1,3-dibromobenzene (3.8 g, 16.08 mmol) was added at a rate to keep amoderate reflux. After Grignard formation was complete (magnesiumconsumed and the reaction cooled),2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.34 g, 0.80 mmol in8 mL of anhydrous diethyl ether) was added drop-wise. The reaction wasrefluxed for 5 h, cooled to room temperature and poured into aseparatory funnel with 20 mL of water. The flask was rinsed with 50 mLof diethyl ether and 3 mL of acetic acid (to dissolve the magnesiumsalts) and added to the seperatory funnel. The layers were separated andthe aqueous layer was collected and concentrated in vacuo. The whitepasty solid was dissolved in 15 mL of pyridine and 10 mL of aceticanhydride. After 20 h at room temperate the reaction was poured into 150mL of water and extracted into dichloromethane (3×150 mL). The organiclayers were combine, washed with 1 N hydrochloric acid (3×50 mL), driedover sodium sulfate, filtered, concentrated and purified by columnchromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) toafford(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol(0.178 g, 0.36 mmol, 45% yield) as a white foam; R_(f) 0.4 (40% ethylacetate-hexane); ¹H NMR (300 MHz, CDCl₃) δ 7.44 (m, 2H) 7.25 (m, 2H),5.27-5.35 (m, 1H), 5.21 (t, J=9.6 Hz, 1H), 5.03 (t, J=9.7 Hz, 1H), 4.36(d, J=9.9 Hz, 1H), 4.23-4.32 (m, 1H) 4.08-4.18 (m, 1H) 3.80-3.85 (m, 1H)2.09 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (s, 3H) ppm; MS [M+H]⁺488.4

EXAMPLE 63 Synthesized in the Same Manner as Example 62, But Replacing1,3 dibromobenzene with 1,4 dibromobenzene

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(4-bromophenyl)-D-glucitol wasobtained (45% yield, white wax). R_(f) 0.3 (40% ethyl acetate-hexane);¹H NMR (300 MHz, CDCl₃) δ 7.47 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7, 2H),5.31 (d, J=9.3 Hz, 1H), 5.21 (t, J=9.9 Hz, 1H), 5.09 (t, J=9.6 Hz, 1H),4.37 (d, J=9.9 Hz, 1H), 4.12-4.33 (m, 2H), 3.83 (m, 1H), 2.09 (s, 3H),2.06 (s, 3H), 2.00 (s, 3H), 1.83 (s, 3H) ppm; MS [M+H]⁺ 488.4

EXAMPLE 64(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3s)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol

(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one(51.3 mg, 0.102 mmol) and(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol(35.5 mg, 0.073 mmol) were dissolved in 2.0 mL of toluene and 0.25 mL ofethanol. 0.075 mL of 4 N potassium carbonate was added to the mixturefollowed by 5.0 mg of tetrakis(triphenylphosphine)palladium(0). Theentire reaction was degassed three times with argon then heated toreflux for 4 h. The reaction was cooled to room temperature, dilutedwith 5 mL of water, and extracted with ethyl acetate (3×25 mL). Theorganic layers were combine, dried over sodium sulfate, filtered,concentrated and purified by column chromatography (12 g silica gel, 5%to 95% ethyl acetate-hexane) to afford 10.5 mg (13%) of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitolas a clear oil.

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3s)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol(10.5 mg, 0.013 mmol) was dissolved in 0.30 mL of methanol and 0.30 mLof triethylamine followed by drop-wise addition of water (0.80 mL). Theyellowish mixture stirred at room temperature overnight. LCMS of thesolution confirmed complete consumption of the starting material andformation of the fully deprotected material. The mixture wasconcentrated in vacuo, and purified by reverse-phase HPLC (Polaris C18-A10μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroaceticacid in water) to afford 2.8 mg (35%) of the desired(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitolas a white powder; ¹H NMR (300 MHz, CD₃OD) δ 7.65 (d, J=11.1 Hz, 2H),7.54-7.23 (m, 10H), 7.05-6.89 (m, 3H), 4.61 (t, J=6.3 Hz, 1H), 4.19 (d,J=9.0 Hz, 1H), 3.87 (d, J=10.7 Hz, 1H), 3.73-3.63 (m, 1H), 3.49-3.36 (m,3H) 3.22-3.18 (m, 2H), 1.89 (m, 4H) ppm; MS [M-OH]⁺ 596.5

EXAMPLE 65(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol

(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one(0.42 g, 0.60 mmol) was dissolved in 15 mL of dioxane in a sealed tube.Bis(pinacolato)diboron (0.17 g, 0.66 mmol), potassium acetate (0.18 g,1.83 mmol), and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (14.6 mg, 0.018 mmol) were addedand the reaction was degassed with argon and heated to 85° C. for 24 h.The mixture was cooled to room temperature diluted with 50 mL of 1:1ethyl acetate-hexane, washed with 100 mL of 0.1 N hydrochloric acid and2×100 mL of brine. The organic layers were collected, partiallyconcentrated to half the volume, filtered through 10 g of silica gel,washed with 50 mL of ethyl acetate and concentrated in vacuo.

The resulting brown oil which is(3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-[2-{[tert-butyl(dimethyl)silyl]oxy}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-phenylazetidin-2-onewas dissolved with(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol in4.0 mL of toluene and 0.5 mL of ethanol. 0.150 mL of 4 N potassiumcarbonate was added followed by 7 mg oftetrakis(triphenylphosphine)palladium(0). The entire reaction wasdegassed three times with argon then heated to reflux for 1.5 h. Afterthis time the reaction was cooled to room temperature and diluted with25 mL of water and extracted with 1:1 hexane-ethyl acetate (3×75 mL).The organic layers were combine, dried over sodium sulfate, filtered,concentrated and purified by column chromatography (12 g silica gel, 5%to 95% ethyl acetate-hexane) to afford 41.6 mg (27%) of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3′-{[tertbutyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitolas a clear oil.

This material was immediately dissolved in 0.80 mL of methanol and 0.80mL of triethylamine followed by dropwise addition of water (2.3 mL). Theyellow mixture was stirred at room temperature for 24 h, extracted with1:1 ethyl acetate-hexane (3×100 mL), dried with sodium sulfate, andconcentrated in vacuo to afford(1S)-1,5-anhydro-1-(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol.

The final deprotection was accomplished by dissolving(1S)-1,5-anhydro-1-(3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitolin 5 mL of acetonitrile, and adding 2.5 mL of 48% hydrofluoric acid. Themixture stirred at room temperature of 1.5 h, neutralized with 70 mL of1 N sodium hydroxide and 50 mL of 1 M sodium phosphate buffer pH 7.4,extracted into ethyl acetate (2×100 mL), washed with saturated sodiumbicarbonate (2×25 mL), dried with sodium sulfate, filtered andconcentrated in vacuo. The crude sample was purified by reverse-phaseHPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1%trifluoroacetic acid in water) to afford 7.9 mg (74%) of the desired(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitolas a white solid; ¹H NMR (300 MHz, CD₃OD) δ 7.49 (dd, J=6.6 Hz, 4H),7.34-7.21 (m, 7H), 7.15 (d, J=7.8 Hz, 1H), 7.07-6.97 (m, 5H), 5.13 (d,J=2.1 Hz, 1H), 4.61 (m, 1H), 4.15 (d, J=9.3 Hz, 1H) 3.90 (d, J=12 Hz,1H), 3.70 (m, 1H) 3.41 (m, 4H), 3.16 (m, 1H), 1.99-1.93 (m, 4H) ppm; MS[M-OH]⁺ 612.6

EXAMPLE 66(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3s)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol

Obtained in a manner similar to Example 65, but using(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4-bromophenyl)-D-glucitol inplace of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol.(1S)-1,5-Anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol(20% yield, white solid). ¹H NMR (300 MHz, CD₃OD) δ 7.49 (dd, J=8.1 Hz,4H), 7.35-7.16 (m, 8H), 7.05-6.97 (m, 4H), 5.15 (d, J=1.8 Hz, 1H), 4.61(m, 1H), 4.16 (d, J=9.6 Hz, 1H), 3.90 (d, J=11.1 Hz, 1H), 3.71 (m, 1H),3.42 (m, 4H), 3.16 (m, 1H), 2.02-1.93 (m, 4H) ppm; MS [M-OH]⁺ 612.6

EXAMPLE 67(2S/2R,3S,4S,6R,7R,8S)-3-O-tert-Butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane

n-Butyllithium (31.5 mL, 41.0 mmol, 1.3 M hexane) was added via additionfunnel to 1,3-dibromobenzene (9.64 g, 41.0 mmol, 4.94 mL) dissolved inanhydrous tetrahydrofuran (30 mL) at −78° C. over 30 min. The additionfunnel was rinsed with anhydrous tetrahydrofuran (15 mL) and thereaction was allowed to stir for 30 min at −78° C. To this solution wasadded5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-glucuronolactone(4.5 g, 13.6 mmol) [prepared according to Tetrahedron Asymmetry 7:9,2761, (1996)] dissolved in 30 mL of anhydrous tetrahydrofuran at −78° C.and the reaction stirred for 2 h. The reaction was quenched by theaddition of saturated ammonium chloride (20 mL) followed by warming toroom temperature. The reaction was poured into ethyl acetate (30 mL) andwater (10 mL) and the layers separated. The aqueous layer was extractedwith ethyl acetate (2×20 mL). The combined organic extracts were driedover anhydrous sodium sulfate, filtered, concentrated and purified bychromatography (1:1 diethyl ether-hexane) to afford a diastereomericmixture of(2S/2R,3S,4S,6R,7R,8S)-3-O-tert-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane (4.77 g, 72% yield) as a colorless viscous oil. R_(f) 0.51(3:1 hexane-ethyl acetate)

EXAMPLE 68(6S)-6-C-(3-Bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose

Sodium borohydride (11.1 mg, 0.29 mmol) was added to(2S/2R,3S,4S,6R,7R,8S)-3-O-tert-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octanedissolved in absolute ethanol (4 mL) at room temperature. The reactionwas stirred at room temperature for 1 h. TLC analysis (3:1 hexane-ethylacetate) indicated that all the starting lactol had been consumed. 1 mLof saturated ammonium chloride solution was added and the reaction wasstirred until the effervescence ceased. The reaction was poured intoethyl acetate (30 mL) and water (10 mL) and the layers separated. Theaqueous layer was extracted 2×20 mL with ethyl acetate. The combinedorganic extracts were dried over anhydrous sodium sulfate, filtered,concentrated and purified by chromatography (3:1 hexane:ethyl acetate)to afford(6S)-6-C-(3-bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose(125 mg, 88% yield) as a white waxy solid. mp 76-77° C.; R_(f) 0.24 (3:1hexane:ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.17 (m, 4H), 5.95(d, J=3.6 Hz, 1H), 4.90 (s, 1H), 4.53 (d, J=3.9 Hz, 1H), 4.32 (d, J=2.7Hz, 1H), 4.09 (dd, J=2.7 Hz, J=8.4 Hz, 1H), 3.75 (d, J=7.2 Hz, 1H),2.76-2.68 (br s, 2H), 1.46 (s, 3H), 1.31 (s, 3H), 0.92 (s, 9H), 0.11 (s,3H), −0.10 (s, 3H) ppm

EXAMPLE 69(6R)-6-C-(3-Bromophenyl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose

Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.14 mL) was addeddropwise to(2S/2R,3S,4S,6R,7R,8S)-3-O-tert-butyldimethylsilyl-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-dioxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane(1.53 g, 3.14 mmol) and glacial acetic acid (188.4 mg, 3.14 mmol, 180μL) in anhydrous tetrahydrofuran (30 mL) at 0° C. The reaction wasstirred for 30 min at 0° C. then warmed to room temperature and stirredan additional 30 min. TLC analysis (3:1 hexane-ethyl acetate) indicatedthat the starting material had been completely consumed. The reactionwas poured into ethyl acetate (30 mL), washed with saturated sodiumbicarbonate (10 mL) and brine (2×10 mL). The aqueous layer was backextracted with ethyl acetate (2×20 mL). The combined organic extractswere dried over anhydrous sodium sulfate, filtered, concentrated andpurified by chromatography (35 g, 40% ethyl acetate-hexane isocratic) toafford(2S/2R,3S,4S,6R,7R,8S)-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-oxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane(1.146 g, 98% yield) as a white solid; R_(f) 0.18 (3:1-hexane-ethylacetate)

Sodium borohydride (116 mg, 3.1 mmol) was added to(2S/2R,3S,4S,6R,7R,8S)-2,3,6,7-tetrahydroxy-6,7-O-isopropylidene-1,5-oxa-2-(3-bromophenyl)-bicyclo[3.3.0]octane (1.15 g, 3.1 mmol) dissolved in absolute ethanol (5 mL) atroom temperature. The reaction was stirred at room temperature for 1 h.TLC analysis (2:1 ethyl acetate-hexane) indicated that all the startinglactol had been consumed. 1 mL of saturated ammonium chloride solutionwas added and the reaction stirred until the effervescence ceased. Thereaction was poured into ethyl acetate (30 mL) and water (10 mL) and thelayers separated. The aqueous layer was extracted with ethyl acetate(2×20 mL). The combined organic extracts were dried over anhydroussodium sulfate, filtered, concentrated and purified by chromatography(2:1 ethyl acetate-hexane to elute the first diastereomer then 100%ethyl acetate) to afford(6R)-6-C-(3-bromophenyl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose(511 mg, 89% yield) as a white solid; mp 172-173° C.; R_(f) 0.19 (2:1ethyl acetate-hexane); ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.62-7.61 (m,1H), 7.42-7.38 (m, 1H), 7.21 (t, J=7.5 Hz, 1H), 5.94 (d, J=3.9 Hz, 1H),4.86 (d, J=4.5 Hz, 1H), 4.48 (d, J=3.3 Hz, 1H), 4.24 (d, J=2.4 Hz, 1H),4.14-4.10 (m, 1H), 3.79-3.74 (m, 1H), 1.38 (s, 3H), 1.30 (s, 3H) ppm

EXAMPLE 70(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one

(3R,4S)-4-(4-Bromophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one(45.1 mg, 0.10 mmol), bis(pinacolato)diboron (27.7 mg, 0.11 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (2.4 mg, 0.003 mmol), and potassium acetate (29.7mg, 0.30 mmol) were dissolved in anhydrous dimethyl sulfoxide (600 μL).The vessel was evacuated and flushed with argon three times then sealedand heated at 80° C. for 16 h. LCMS analysis indicated that somestarting material remained so an additional aliquot of catalyst andbis(pinacolato)diboron were added, the solution degassed and heatingcontinued for 2 h. The reaction was diluted into dichloromethane (30 mL)and filtered through a plug of Celite®. The filtrate was washed 2×10 mLwith water. The combined aqueous washed were back extracted with 3×10 mLdichloromethane. The combined organic phase was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The product waspurified by chromatography (12 g silica gel, 20-50% ethylacetate-hexane) to afford(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one(41.9 mg, 85% yield) as a tan foam; R_(f) (1:1 hexane-ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.1 Hz, 1H), 7.35-7.18 (m, 9H),7.04-6.97 (m, 3H), 4.70 (t, J=5.7 Hz, 1H), 4.65 (d, J=2.1 Hz, 1H), 3.08(dt, J=7.7, 2.5, 1H), 2.02-1.87 (m, 4H), 1.33 (s, 12H) ppm

EXAMPLE 71(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose

(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one(26.8 mg, 0.05 mmol),(6S)-6-C-(3-bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose(18.1 mg, 0.04 mmol), and potassium carbonate (40 μL, 4 N aqueous) weredissolved in 1:1 toluene:ethanol (1 mL total volume). The solution wasdegassed by evacuating the vessel and flushing with argon three times.Tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.002 mmol) was addedand the solution was degassed twice. The reaction was heated at 85° C.for 1 h. LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicatedconsumption of the starting glycoside. The reaction was diluted intoethyl acetate (30 mL) and washed with water (2×10 mL). The combinedaqueous washes were back extracted with ethyl acetate (2×10 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, concentrated in vacuo and purified by chromatography (12 gsilica gel, 20-50% ethyl acetate-hexane) to afford(6S)-6-O-[tert-butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose(13.5 mg, 45% yield) as a white foam; R_(f) 0.23 (1:1 hexane-ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.22 (m, 13H), 7.07-6.98 (m,4H), 5.97 (d, J=3.9 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.73 (t, J=6.3 Hz,1H), 4.69 (d, J=2.1 Hz, 1H), 4.54 (d, J=3.9 Hz, 1H), 4.37 (d, J=2.4 Hz,1H), 3.87-3.86 (m, 1H), 3.13-3.09 (m, 1H), 2.04-1.86 (m, 4H), 1.43 (s,3H), 1.31 (s, 3H), 0.94 (s, 9H), 0.12 (s, 3H), −0.09 (s, 3H) ppm

(6S)-6-O-[tert-Butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose(13.5 mg, 0.017 mmol) was dissolved in acetonitrile (5 mL) in apolypropylene centrifuge tube. 48% Hydrofluoric acid (500 μL) was addedat room temperature and the reaction was stirred for 16 h monitoring byLCMS. Upon completion, 1 equivalent of solid sodium carbonate (1.27 g,12 mmol) was added and just enough water to dissolve the solid. Thereaction was diluted into ethyl acetate (20 mL) and the layersseparated. The aqueous solution was extracted with ethyl acetate (3×10mL). The combined organic extracts were washed with saturated sodiumcarbonate (2×10 mL), dried over anhydrous sodium sulfate, filtered,concentrated in vacuo and purified by reverse-phase HPLC (Polaris C18-A10μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroaceticacid in water) to afford(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose(5.5 mg, 51%); ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.64-7.58 (m, 2H),7.48-7.21 (m, 12H), 7.08-6.98 (m, 3H), 5.12-5.07 (m, 1.4H), 4.73 (d,J=2.4 Hz, 1H), 4.66 (t, J=5.7 Hz, 1H), 4.39 (d, J=7.5 Hz, 0.6H), 4.00(dd, J=1.5 Hz, J=9.6 Hz, 0.6H), 3.76-3.56 (m), 3.23-3.10 (m, 1.5H),2.01-1.90 (m, 4H) ppm; MS [M+H]⁺ 630.0

EXAMPLE 72(6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose

Obtained in a manner similar to Example 71 but using as startingmaterials the products from Examples 68 and 70.(6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose(2.4 mg, 53% yield); ¹H NMR (300 MHz, CDCl₃/0.1% CD₃OD) δ 7.64-7.58 (m,2H), 7.49-7.23 (m, 12H), 7.08-6.98 (m, 3H), 5.06 (d, J=3.6 Hz, 0.6H),4.91 (d, J=6.0 Hz, 1H), 4.72 (d, J=4.8 Hz, 1H), 4.66 (t, J=5.4 Hz, 1H),4.42 (d, J=7.8 Hz, 0.4H), 4.07-4.02 (m, 1H), 3.69-3.66 (m, 1H),3.16-3.11 (m, 1H), 1.96-1.91 (m, 4H) ppm; MS [M+H]⁺ 630.0

EXAMPLE 73(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose

(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-[2-{[tert-butyl(dimethyl)silyl]oxy}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-phenylazetidin-2-one(53.0 mg, 0.07 mmol),(6S)-6-C-(3-bromophenyl)-6-O-[tert-butyl(dimethyl)silyl]-1,2-O-(1-methylethylidene)-α-D-glucofuranose(24.1 mg, 0.05 mmol), and potassium carbonate (50 μL, 4 N aqueoussolution) were dissolved in 1:1 toluene:ethanol (1 mL total volume). Thesolution was degassed by evacuating the vessel and flushing with argonthree times. Tetrakis(triphenylphosphine)palladium (4.0 mg, 0.003 mmol)was added and the solution degassed twice. The reaction was heated at85° C. for 1 h. LCMS and TLC (1:1 hexane-ethyl acetate) analysisindicated consumption of the starting glycoside. The reaction wasdiluted into ethyl acetate (30 mL) and washed with water (2×10 mL). Thecombined aqueous washes were back extracted with ethyl acetate (2×10mL). The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, concentrated in vacuo, and purified by chromatography(12 g silica gel, 5-50% ethyl acetate-hexane) to afford(6S)-6-O-[tert-butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranose(10.5 mg, 20% yield) as a white foam; ¹H NMR (300 MHz, CDCl₃) δ7.44-7.18 (m, 13H), 7.05-6.93 (m, 3H), 5.97 (d, J=3.9 Hz, 1H), 5.03 (d,J=2.1 Hz, 1H), 4.95 (d, J=2.4 Hz, 1H), 4.67 (m, 1H), 4.56 (t, J=4.8 Hz,1H), 4.38 (m, 1H), 4.10 (dd, J=7.6, 3.0 Hz, 1H), 3.87 (m, 1H), 3.12 (m,1H), 1.94-1.89 (m, 4H), 1.44 (s, 3H), 1.31 (s, 3H), 0.93 (s, 9H), 0.86(s, 9H), 0.11 (s, 3H), 0.01 (s, 3H), −0.11 (s, 3H), −0.16 (s, 3H) ppm

(6S)-6-O-[tert-Butyl(dimethyl)silyl]-6-C-(4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-1,2-O-(1-methylethylidene)-α-D-glucofuranosewas dissolved in acetonitrile (5 mL) in a polypropylene centrifuge tube.48% Hydrofluoric acid (750 μL) was added at room temperature and thereaction stirred for 16 h monitoring progress by LCMS. Upon completion,1 equivalent of solid sodium carbonate (1.91 g, 18 mmol) was added andjust enough water to dissolve the solid. The reaction was diluted intoethyl acetate (20 mL) and the layers separated. The aqueous solution wasextracted with ethyl acetate (3×10 mL). The combined organic extractswere washed with saturated sodium carbonate (2×10 mL), dried overanhydrous sodium sulfate, filtered, concentrated in vacuo and purifiedby reverse-phase HPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 95%acetonitrile-0.1% trifluoroacetic acid in water) to afford(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose(17.8 mg); ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.52-6.83 (m, 16H), 5.05-5.00(m, 2H), 4.50 (m, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.72-3.59 (m, 2H),2.91 (m, 1H), 1.95-1.77 (m, 4H) ppm; MS [M-OH]⁺ 627.8

EXAMPLE 74(6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose

Obtained in a manner similar to Example 73. Purified by reverse-phaseHPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1%trifluoroacetic acid in water) to afford(6R)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose(4.1 mg, 70% yield); ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.55-6.90 (m, 16H),5.08-2.06 (m, 1H), 5.01-5.00 (m, 1H), 4.86 (d, J=4.5 Hz, 1H), 4.60 (t,J=5.1 Hz, 1H), 4.39 (d, J=8.1 Hz, 1H), 4.02-3.97 (m, 1H), 3.70-3.64 (m,1H), 3.52-3.49 (m, 1H), 1.96-1.85 (m, 4H) ppm; MS [M-OH]⁺ 627.8

EXAMPLE 75(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol

(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose(7.1 mg, 0.01 mmol) was dissolved in 80:20 acetonitrile-water (1 mL).Sodium borohydride (0.4 mg, 0.01 mmol) was added at room temperature andthe reaction was stirred for 30 min monitoring by LCMS. Upon completion,the reaction was diluted with 80:20 acetonitrile:water (3 mL) thenfiltered through a Whatman 0.45 μM glass microfiber filter and purifiedby reverse-phase HPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 95%acetonitrile-0.1% trifluoroacetic acid in water) to afford(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol(1.4 mg, 22% yield). ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.37-6.89 (m, 16H),5.08 (d, J=2.4 Hz, 1H), 4.97-4.95 (m, 1H), 4.60 (t, J=6.0 Hz, 1H), 3.92(m, 1H), 3.76-3.56 (m, 6H), 2.01-1.82 (m, 4H) ppm; MS [M-OH]⁺ 629.8.

EXAMPLE 766-O-(4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose

Diethylazodicarboxylate (192.4 mg, 1.11 mmol, 172 μL) was addeddrop-wise at 0° C. to 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose (350.0mg, 1.01 mmol), 3-bromophenol (174.0 mg, 1.11 mmol), andtriphenylphosphine (115.0 mg, 0.44 mmol) dissolved in drytetrahydrofuran (2 mL). The reaction was stirred for 16 h warming toroom temperature. The reaction was diluted into diethyl ether (30 mL)and washed with 5% sodium bisulfate (2×10 mL). The separated organicsolution was dried over anhydrous sodium sulfate, filtered, concentratedin vacuo and purified by chromatography (20% ethylacetate-dichloromethane) to afford1,2,3,4-tetra-O-acetyl-6-O-(3-bromophenyl)-β-D-glucopyranose (357 mg,71% yield)

Triethylamine (1 mL) was added at room temperature to1,2,3,4-tetra-O-acetyl-6-O-(3-bromophenyl)-β-D-glucopyranose (200 mg,0.40 mmol) dissolved in 5:1 methanol-water (6 mL). The reaction progresswas monitored by LCMS and TLC (20% ethyl acetate-dichloromethane). Uponcompletion, the solvents were removed in vacuo to afford6-O-(3-bromophenyl)-β-D-glucopyranose which was carried on withoutfurther purification.

tert-Butyldimethylsilyl trifluoromethanesulfonate (442 mg, 1.67 mmol,383 μL) was added dropwise at 0° C. to6-O-(3-bromophenyl)-β-D-glucopyranose and 4-dimethylaminopyridine (219mg, 1.79 mmol) dissolved in dichloromethane (3 mL). The reaction wasstirred for 16 h warming to room temperature. The reaction was dilutedinto dichloromethane (30 mL) and washed with 5% sodium bisulfate (2×10mL). The separated organic solution was dried over anhydrous sodiumsulfate, filtered, concentrated in vacuo and purified by chromatography(50% ethyl acetate:hexane) to afford a6-O-(3-bromophenyl)-β-D-glucopyranosebis-O-[tert-butyl(dimethyl)silyl]ether (98.9 mg, 44% yield); R_(f)=0.14(50% ethyl acetate-hexane)

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one(141.5 mg, 0.27 mmol), 6-O-(3-bromophenyl)-β-D-glucopyranosebis-O-[tert-butyl(dimethyl)silyl]ether (98.9 mg, 0.18 mmol), andpotassium carbonate (175 μL, 2 M aqueous solution) were dissolved in 1:1toluene-ethanol (1 mL total volume). The solution was degassed byevacuating the vessel and flushing with argon three times.Tetrakis(triphenylphosphine)palladium (10.0 mg, 0.009 mmol) was addedand the solution degassed twice. The reaction was heated at 85° C. for 1h. LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicatedconsumption of the starting glycoside. The reaction was diluted intoethyl acetate (30 mL) and washed with water (2×10 mL). The combinedaqueous washes were back extracted with ethyl acetate (2×10 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, concentrated in vacuo and purified by chromatography (12 gsilica gel, 50% ethyl acetate-hexane) to afford6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-β-D-glucopyranosebis-O-[tert-butyl(dimethyl)silyl]ether (113 mg, 74% yield). ¹H NMR (300MHz, CDCl₃) δ 7.56 (d, J=7.8 Hz, 2H), 7.36-7.10 (m, 8H), 7.01-6.80 (m,6H), 4.70 (t, J=5.4 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.56 (d, J=6.9 Hz,1H), 4.35-4.32 (m, 1H), 4.16-4.07 (m, 1H), 3.68-3.58 (m, 2H), 3.51-3.46(m, 1H), 3.38-3.32 (m, 1H), 3.11-3.09 (m, 1H), 1.98-1.88 (m, 4H), 0.91(s, 9H), 0.91 (s, 9H), 0.14 (s, 6H), 0.13 (s, 6H) ppm

6-O-(4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranosebis-O-[tert-butyl(dimethyl)silyl]ether (82.3 mg, 0.09 mmol) wasdissolved in acetonitrile (10 mL) in a polypropylene centrifuge tube.48% Hydrofluoric acid (1 mL) was added at room temperature and thereaction monitored by LCMS. Upon completion, 1 equivalent of solidsodium carbonate (2.54 g, 24 mmol) was added and just enough water todissolve the solid. The reaction was diluted into ethyl acetate (20 mL)and the layers separated. The aqueous solution was extracted with ethylacetate (3×10 mL). The combined organic extracts were washed withsaturated sodium carbonate (2×10 mL), dried over anhydrous sodiumsulfate, filtered, concentrated in vacuo and purified by reverse phasepreparative HPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 95%acetonitrile-0.1% trifluoroacetic acid in water) to afford6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranose(54.3 mg, 89% yield). ¹H NMR (300 MHz, CDCl₃/1% CD₃OD) δ 7.58 (d, J=7.8Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5H), 5.23(d, J=3.9 Hz, 0.6H), 4.71 (d, J=1.8 Hz, 1H), 4.66 (t, J=5.7 Hz, 1H),4.58 (d, J=8.1 Hz, 0.4H), 4.40-4.30 (m, 1H), 4.25-4.14 (m, 1H),3.57-3.48 (m, 2H), 3.16-3.11 (m, 1H), 2.04-1.85 (m, 4H) ppm; MS [M-OH]⁺630.0

EXAMPLE 77 Methyl6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside

Diethylazodicarboxylate (76.2 mg, 0.44 mmol, 68 μL) was added drop-wiseto methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (184.8 mg, 0.40 mmol),3-bromophenol (72.3 mg, 0.42 mmol), and triphenylphosphine (115.0 mg,0.44 mmol) dissolved in dry tetrahydrofuran (2 mL) at 0° C. The reactionwas stirred for 16 h warming to room temperature. The reaction wasdiluted into dichloromethane (30 mL) and washed with 5% sodium bisulfate(2×10 mL). The separated organic solution was dried over anhydroussodium sulfate, filtered, concentrated in vacuo and purified bychromatography (20% ethyl acetate-dichloromethane) to afford methyl2,3,4-tri-O-benzyl-6-O-(3-bromophenyl)-α-D-glucopyranoside (216 mg, 87%yield)

(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one(64.1 mg, 0.12 mmol), methyl2,3,4-tri-O-benzyl-6-O-(3-bromophenyl)-D-glucopyranoside (54.6 mg, 0.09mmol), and potassium carbonate (88 μL, 2 M aqueous solution) weredissolved in 1:1 toluen-ethanol (1 mL total volume). The solution wasdegassed by evacuating the vessel and flushing with argon three times.Tetrakis(triphenylphosphine)palladium (5.1 mg, 0.004 mmol) was added andthe solution degassed twice. The reaction was heated at 85° C. for 1 h.LCMS and TLC (1:1 hexane-ethyl acetate) analysis indicated consumptionof the starting glycoside. The reaction was diluted into ethyl acetate(30 mL) and washed with water (2×10 mL). The combined aqueous washeswere back extracted with ethyl acetate (2×10 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered,concentrated in vacuo and purified by chromatography (12 g silica gel,20% to 50% ethyl acetate-hexane) to afford methyl2,3,4-tri-O-benzyl-6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside(70.0 mg, 85% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=8.1 Hz, 2H),7.39-6.84 (m, 29H), 5.01 (d, J=10.8 Hz, 1H), 4.89-4.80 (m, 3H),4.73-4.64 (m, 4H), 4.52 (d, J=11.1 Hz, 1H), 4.15-4.12 (m, 2H), 4.08-4.1(m, 1H), 3.94-3.90 (m, 1H), 3.77-3.71 (m, 1H), 3.62 (dd, J=3.6 Hz, J=9.6Hz, 1H), 3.39 (s, 3H), 3.13-3.10 (m, 1H), 2.03-1.89 (m, 4H) ppm

Methyl2,3,4-tri-O-benzyl-6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside(70 mg, 0.08 mmol) was dissolved in absolute ethanol (3 mL). 10% Pd/C(wet, 14% w/w) was added and the vessel sealed. The solution wasdegassed by evacuation and flushing with hydrogen gas at balloonpressure. The reaction was monitored by TLC (1:1 hexane-ethyl acetate).Upon completion, the catalyst was filtered by passing through a plug ofCelite® and washing with additional ethanol. The filtrate wasconcentrated in vacuo and purified by preparative HPLC (Polaris C18-A10μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroaceticacid in water) affording methyl6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside(18.1 mg, 36% yield); ¹H NMR (300 MHz, CDCl₃/1% CD₃OD) δ 7.58 (d, J=8.4Hz, 2H), 7.38-7.23 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5H), 4.80(d, J=3.9 Hz, 1H), 4.70 (d, J=2.4 Hz, 1H), 4.67 (t, J=5.7 Hz, 1H),4.37-4.33 (m, 1H), 4.26-4.21 (m, 1H), 3.92-3.87 (m, 1H), 3.74-3.45 (m,3H), 3.42 (s, 3H), 3.18-3.10 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M-OH]⁺644.0

EXAMPLE 786-O-(4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucitol

Sodium borohydride (1.6 mg, 0.04 mmol) was added to6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose(26.3 mg, 0.04 mmol) dissolved in 80:20 acetonitrile-water (1 mL) atroom temperature. The reaction was stirred for 10 min at roomtemperature monitoring by LCMS. Upon completion, the reaction wasdiluted with 50:50 acetonitrile:water (3 mL) and filtered through aWhatman 0.45 μM glass microfiber filter then purified by preparativeHPLC (Polaris C18-A 10μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1%trifluoroacetic acid in water) affording6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucitol(21.2 mg, 80% yield). ¹H NMR (300 MHz, CDCl₃/1% CD₃OD) δ 7.58 (d, J=8.1Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.15 (m, 2H), 7.04-6.92 (m, 5H), 4.71(d, J=2.1 Hz, 1H), 4.68 (t, J=6.3 Hz, 1H), 4.31-4.27 (m, 1H), 0.19-4.14(m, 1H), 4.08-4.02 (m, 1H), 3.97-3.95 (m, 1H), 3.86-3.65 (m, 4H),3.14-3.12 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M+HCO₂ ⁻]⁻ 694.0

Illustrated in Scheme IV is the general method for the preparation ofcholesterol absorption inhibitors of general formula IV-3. Imines IV-2are made by refluxing anilines with the appropriate aldehydes inisopropanol. Condensation of imine IV-2 with the ester enolate ofcompound IV-I affords the azetidinone IV-3. In the case where X issulfur, one equivalent of an appropriate oxidizing agent such as MCPBAcan be used to convert to the sulfoxide, two equivalents can be used tosynthesize the sulfone. Where X is nitrogen, one equivalent of anappropriate oxidizing agent can be used to convert the secondary amineto a hydroxylamine (following deprotection).

The following examples were also prepared according to the methodsdescribed above:

EXAMPLE 81

-   (3R,4S)-4-(3′,4′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 82

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(methylthio)biphenyl-4-yl]    azetidin-2-one

EXAMPLE 83

-   (3R,4S)-4-[3′-(dimethylamino)biphenyl-4-yl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 84

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-vinylbiphenyl-4-yl)azetidin-2-one

EXAMPLE 85

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-5-methoxybiphenyl-2-carbaldehyde

EXAMPLE 86

-   (3R,4S)-4-(3′-aminobiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 87

-   (3R,4S)-4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 88

-   (4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-yl)acetic    acid

EXAMPLE 89

-   methyl    4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-carboxylate

EXAMPLE 90

-   (3R,4S)-4-(3′,5′-dimethylbiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 91

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(2-naphthyl)phenyl]azetidin-2-one

EXAMPLE 92

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3′-(trifluoromethyl)biphenyl-4-yl]azetidin-2-one

EXAMPLE 93

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-methylbiphenyl-4-yl)azetidin-2-one

EXAMPLE 94

-   (3R,4S)-4-(4′-fluoro-3′-methylbiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 95

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl    β-L-glucopyranoside

EXAMPLE 96

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′,3′,4′-trimethoxybiphenyl-4-yl)azetidin-2-one

EXAMPLE 97

-   (3R,4S)-4-(2′,4′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 98

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(2′-methylbiphenyl-4-yl)azetidin-2-one

EXAMPLE 99

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-carbaldehyde

EXAMPLE 100

-   (3R,4S)-4-(3′-ethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 101

-   (3R,4S)-4-(4′-ethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 102

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxy-3′-methoxybiphenyl-4-yl)azetidin-2-one

EXAMPLE 103

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-propoxybiphenyl-4-yl)azetidin-2-one

EXAMPLE 104

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-5-hydroxybiphenyl-2-carbaldehyde

EXAMPLE 105

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-isopropoxybiphenyl-4-yl)azetidin-2-one

EXAMPLE 106

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-4-hydroxybiphenyl-3-carboxylic    acid

EXAMPLE 107

-   (3R,4S)-4-(3′,5′-dimethoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 108

-   (3R,4S)-4-(2′,4′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 109

-   (3R,4S)-4-(3′-butoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 110

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-3-hydroxybiphenyl-4-carboxylic    acid

EXAMPLE 111

-   (3R,4S)-4-(3′-fluoro-5′-methoxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 112

-   (3R,4S)-4-(3′-fluoro-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 113

-   (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-L-glucitol

EXAMPLE 114

-   (3R,4S)-4-(3′,5′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 115

-   (4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)boronic    acid

EXAMPLE 116

-   (1R)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-4-yl)-L-glucitol

EXAMPLE 117

-   2,6-anhydro-1-deoxy-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glycero-D-gulo-heptitol

EXAMPLE 118

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-sulfonic    acid

EXAMPLE 119

-   (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-mercaptobiphenyl-4-yl)azetidin-2-one

EXAMPLE 120

-   4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-N,N,N-trimethylbiphenyl-3-aminium

EXAMPLE 121

-   (3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

EXAMPLE 122

-   (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic    acid

EXAMPLE 123

-   (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[3-hydroxy-3′-(methylsulfonyl)biphenyl-4-yl]-1-phenylazetidin-2-one

EXAMPLE 124

-   (3R,4S)-1-biphenyl-4-yl-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one

EXAMPLE 125

-   (3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

EXAMPLE 126

-   Dimethyl    [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate

prepared in analogous manner to dimethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate(Example 60) starting with 4-chlorophenol instead of 3-chlorophenol.Dimethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonateproduct was obtained as a light yellow oil (90%); ¹H NMR (300 MHz,CDCl₃) δ 7.86-7.95 (m, 2H), 7.84-7.82 (m, 2H), 7.43-7.50 (m, 1H), 3.76(s, 3H), 3.73 (s, 3H), 1.34 (s, 12H) ppm; MS [M+H] 312, [2M+H] 625.

EXAMPLE 127(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonicacid

prepared in analogous manner to Example 61 using dimethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate(Example 126) in the reaction scheme instead of dimethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate(Example 60). Final purification by reverse-phase HPLC (Polaris C18-A110 250×21.2 mm column, 30% to 59% acetonitrile-0.1% trifluoroaceticacid in water) afforded(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonicacid as a white powder (62%); ¹H NMR (300 MHz, CD₃OD) δ 7.8 (dd, J=8.0,13.0 Hz, 1H), 7.68 (dd, J=3.2, 8.0 Hz, 1H), 6.9-7.4 (m, 14H), 5.17 (d,J=2.1 Hz, 1H), 4.60-4.66 (m, 1H), 3.13-3.22 (m, 1H), 1.8-2.1 (m, 4H)ppm; MS [M−H] 546, [2M−H] 1093.

EXAMPLE 128 Sodium4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate

5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenylacetate (850 mg, 1.36 mmol) and 4-thioanisoleboronic acid (252 mg, 1.50mmol) were dissolved in dioxane (13.6 mL). Cesium carbonate (882 mg,2.71 mmol) and solid bis(1-adamantylamine)palladium(0) (113 mg, 0.21mmol) were added and the vessel was vacuum/nitrogen purged (3×). Thereaction was stirred vigorously for 4 h at 80° C. under a nitrogenatmosphere and then cooled and reacted with acetic anhydride (0.70 mL,7.3 mmol) and 4-dimethylamino-pyridine (185.6 mg, 1.52 mmol). After 15min, the mixture was poured into 1.0 N hydrochloric acid (60 mL),extracted with 1:1 ethyl acetate-hexane (60 mL), washed with brine (60mL), dried over sodium sulfate, filtered, concentrated and purified bychromatography (40 g silica gel, 5% to 50% ethyl acetate-hexane) toafford4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-4′-(methylthio)biphenyl-3-ylacetate (478 mg, 52% yield) as a white foam; R_(f) 0.41 (1:4 ethylacetate-hexane).

4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-4′-(methylthio)biphenyl-3-ylacetate (478 mg, 0.713 mmol) was dissolved in dichloromethane (20 mL)and cooled to 0° C. 3-Chlorobenzenecarbo-peroxoic acid (134.5 mg, 0.779mmol) was added in portions while monitoring by TLC and LCMS to make thearylsulfoxide. Once addition was complete the reaction was poured intoquarter saturated sodium bicarbonate solution (60 mL), extracted withdichloromethane (60 mL) and ethyl acetate (60 mL), the combined organiclayers were dried over sodium sulfate, filtered and concentrated withtoluene. The residue was dissolved in dichloromethane (10 mL) and thePummerer rearrangement was effected by the addition of trifluoroaceticanhydride (250 μL, 372 mg, 1.77 mmol). The reaction was stirred at roomtemperature for 8.5 h and then concentrated with toluene and dilutedwith a solution of degassed methanol (3.0 mL), triethylamine (3.0 mL)and water (1.0 mL). After 2.75 h the golden yellow solution wasconcentrated, transferred into a polypropylene Falcon® tube withacetonitrile (10.0 mL) and diluted with 48% hydrofluoric acid (1.0 mL).The reaction was stirred for 4 h at room temperature and then pouredinto 0.5 M potassium phosphate (50 mL), extracted with ethyl acetate (60mL), washed with water (60 mL) and brine (60 mL), dried over sodiumsulfate, filtered, concentrated and purified by chromatography (40 gsilica gel, 10% to 100% ethyl acetate-hexane) to afford a mixture ofcompounds (some impurities and oxidized desired material). The residuewas used as is in the next step.

The residue was dissolved in dichloromethane (10 mL) and added drop-wiseto a solution of 3-chlorobenzenecarboperoxoic acid (489 mg, 2.83 mmol)in dichloromethane (10 mL). Dichloromethane (5 mL) was used to helptransfer the material and the mixture was stirred at room temperaturefor 15 min. The reaction was quenched by addition of triethylamine (4mL), concentrated, dissolved in methanol, filtered through a 0.45μWhatman® filter, concentrated again, purified by reverse-phase HPLC(Polaris C18-A 10μ 250×21.2 mm column, 5% to 100% acetonitrile-0.1%triethylamine in water) and treated with Dowex® sodium ion exchangeresin to afford sodium4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate(249.0 mg, 57% yield) as a light pale purple solid; ¹H NMR (300 MHz,CD₃OD) δ 7.88 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.35-7.19 (m,7H), 7.14-7.11 (m, 2H), 7.03-6.97 (m, 3H), 5.14 (d, J=2.2 Hz, 1H),4.63-4.59 (m, 1H), 3.17-3.08 (m, 1H), 2.04-1.87 (m, 4H) ppm; MS [M-Na]546.0

Also within the invention are compounds described by Table 3, togetherwith Table 4 and Formula VIII which is shown below.

In these embodiments, R¹ and R² are independently chosen from H, F, CN,Cl, CH₃, OCH₃, OCF₃, OCF₂H, CF₃, CF₂H, and CH₂F; R⁴ is chosen from H,Cl, CH₃, OCH₃, OH, B(OH)₂, and SH; R⁵ is chosen from OH, SO₃H, PO₃H₂,CH₂OH, COOH, CHO, D-glucitol, a C-glysosyl compound and a sugar and onlyone R substitution is allowed on any aromatic ring. For example, whereR⁵ is —OH, all of the other substituents on the corresponding aromaticring are H. Of course, where a given R group is H (e.g., R¹) all of thesubstituents on the corresponding aromatic ring are also H. In Table 4when the R⁴ substituent position is defined as 3-, the substitutionoccurs at the position ortho to the azetidinone ring. In Table 4 whenthe R⁴ substituent position is defined as 2-, the substitution occurs atthe position meta to the azetidinone ring.

Each row in Table 3 defines a unique subset of R group substituentswhich can be systematically substituted in an iterative fashion intoFormula VIII at the positions specified by each row of Table 4 togenerate specific compounds within Formula VIII. For example, in Table3, row 1, R¹ is H, R² is F, R⁴ is OH, and R⁵ is OH. Substituting thisset of R groups into Formula VIII according to the placement defined byrow 1 of Table 4 (i.e., R¹ is ortho, R² is ortho, R⁴ is 3- and R⁵ isortho) yields

(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Similarly,(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-oneis disclosed by the using values in Table 3, row 1 to substitute FormulaVIII according to Table 4, row 2.

Tables 5-20 comprise the compounds disclosed by substituting thesubstituents listed in Table 3 rows 1-16 into Formula VIII according tothe placement defined by each row in Table 4. It should be understoodthat the compounds listed in Tables 5-20 are only a small subset of thecompounds described by the systematic iterative substitution of thesubstituents in each row of Table 3 into generic Formula VIII accordingto the placement defined by each row of Table 4.

TABLE 3 Row R1 R2 R4 R5 1 H F OH OH 2 H F OH D-glucitol 3 H F OH SO₃H 4H F OH PO₃H₂ 5 H H OH OH 6 H H OH D-glucitol 7 H H OH SO₃H 8 H H OHPO₃H₂ 9 H Cl OH OH 10 H Cl OH D-glucitol 11 H Cl OH SO₃H 12 H Cl OHPO₃H₂ 13 F H OH OH 14 F H OH D-glucitol 15 F H OH SO₃H 16 F H OH PO₃H₂17 F F OH OH 18 F F OH D-glucitol 19 F F OH SO₃H 20 F F OH PO₃H₂ 21 F ClOH OH 22 F Cl OH D-glucitol 23 F Cl OH SO₃H 24 F Cl OH PO₃H₂ 25 Cl H OHOH 26 Cl H OH D-glucitol 27 Cl H OH SO₃H 28 Cl H OH PO₃H₂ 29 Cl F OH OH30 Cl F OH D-glucitol 31 Cl F OH SO₃H 32 Cl F OH PO₃H₂ 33 Cl Cl OH OH 34Cl Cl OH D-glucitol 35 Cl Cl OH SO₃H 36 Cl Cl OH PO₃H₂ 37 H H H OH 38 HH H D-glucitol 39 H H H SO₃H 40 H H H PO₃H₂ 41 H H H CHO 42 H H H COOH43 H H H CH₂OH 44 H H H sugar 45 H H H C-glycosyl compound 46 H H OH CHO47 H H OH COOH 48 H H OH CH₂OH 49 H H OH sugar 50 H H OH C-glycosylcompound 51 H H CH₃ OH 52 H H CH₃ D-glucitol 53 H H CH₃ SO₃H 54 H H CH₃PO₃H₂ 55 H H CH₃ CHO 56 H H CH₃ COOH 57 H H CH₃ CH₂OH 58 H H CH₃ sugar59 H H CH₃ C-glycosyl compound 60 H H Cl OH 61 H H Cl D-glucitol 62 H HCl SO₃H 63 H H Cl PO₃H₂ 64 H H Cl CHO 65 H H Cl COOH 66 H H Cl CH₂OH 67H H Cl sugar 68 H H Cl C-glycosyl compound 69 H H B(OH)₂ OH 70 H HB(OH)₂ D-glucitol 71 H H B(OH)₂ SO₃H 72 H H B(OH)₂ PO₃H₂ 73 H H B(OH)₂CHO 74 H H B(OH)₂ COOH 75 H H B(OH)₂ CH₂OH 76 H H B(OH)₂ sugar 77 H HB(OH)₂ C-glycosyl compound 78 H H SH OH 79 H H SH D-glucitol 80 H H SHSO₃H 81 H H SH PO₃H₂ 82 H H SH CHO 83 H H SH COOH 84 H H SH CH₂OH 85 H HSH sugar 86 H H SH C-glycosyl compound 87 H H OCH₃ OH 88 H H OCH₃D-glucitol 89 H H OCH₃ SO₃H 90 H H OCH₃ PO₃H₂ 91 H H OCH₃ CHO 92 H HOCH₃ COOH 93 H H OCH₃ CH₂OH 94 H H OCH₃ sugar 95 H H OCH₃ C-glycosylcompound 96 H F H OH 97 H F H D-glucitol 98 H F H SO₃H 99 H F H PO₃H₂100 H F H CHO 101 H F H COOH 102 H F H CH₂OH 103 H F H sugar 104 H F HC-glycosyl compound 105 H F OH CHO 106 H F OH COOH 107 H F OH CH₂OH 108H F OH sugar 109 H F OH C-glycosyl compound 110 H F CH₃ OH 111 H F CH₃D-glucitol 112 H F CH₃ SO₃H 113 H F CH₃ PO₃H₂ 114 H F CH₃ CHO 115 H FCH₃ COOH 116 H F CH₃ CH₂OH 117 H F CH₃ sugar 118 H F CH₃ C-glycosylcompound 119 H F Cl OH 120 H F Cl D-glucitol 121 H F Cl SO₃H 122 H F ClPO₃H₂ 123 H F Cl CHO 124 H F Cl COOH 125 H F Cl CH₂OH 126 H F Cl sugar127 H F Cl C-glycosyl compound 128 H F B(OH)₂ OH 129 H F B(OH)₂D-glucitol 130 H F B(OH)₂ SO₃H 131 H F B(OH)₂ PO₃H₂ 132 H F B(OH)₂ CHO133 H F B(OH)₂ COOH 134 H F B(OH)₂ CH₂OH 135 H F B(OH)₂ sugar 136 H FB(OH)₂ C-glycosyl compound 137 H F SH OH 138 H F SH D-glucitol 139 H FSH SO₃H 140 H F SH PO₃H₂ 141 H F SH CHO 142 H F SH COOH 143 H F SH CH₂OH144 H F SH sugar 145 H F SH C-glycosyl compound 146 H F OCH₃ OH 147 H FOCH₃ D-glucitol 148 H F OCH₃ SO₃H 149 H F OCH₃ PO₃H₂ 150 H F OCH₃ CHO151 H F OCH₃ COOH 152 H F OCH₃ CH₂OH 153 H F OCH₃ sugar 154 H F OCH₃C-glycosyl compound 155 H Cl H OH 156 H Cl H D-glucitol 157 H Cl H SO₃H158 H Cl H PO₃H₂ 159 H Cl H CHO 160 H Cl H COOH 161 H Cl H CH₂OH 162 HCl H sugar 163 H Cl H C-glycosyl compound 164 H Cl OH CHO 165 H Cl OHCOOH 166 H Cl OH CH₂OH 167 H Cl OH sugar 168 H Cl OH C-glycosyl compound169 H Cl CH₃ OH 170 H Cl CH₃ D-glucitol 171 H Cl CH₃ SO₃H 172 H Cl CH₃PO₃H₂ 173 H Cl CH₃ CHO 174 H Cl CH₃ COOH 175 H Cl CH₃ CH₂OH 176 H Cl CH₃sugar 177 H Cl CH₃ C-glycosyl compound 178 H Cl Cl OH 179 H Cl ClD-glucitol 180 H Cl Cl SO₃H 181 H Cl Cl PO₃H₂ 182 H Cl Cl CHO 183 H ClCl COOH 184 H Cl Cl CH₂OH 185 H Cl Cl sugar 186 H Cl Cl C-glycosylcompound 187 H Cl B(OH)₂ OH 188 H Cl B(OH)₂ D-glucitol 189 H Cl B(OH)₂SO₃H 190 H Cl B(OH)₂ PO₃H₂ 191 H Cl B(OH)₂ CHO 192 H Cl B(OH)₂ COOH 193H Cl B(OH)₂ CH₂OH 194 H Cl B(OH)₂ sugar 195 H Cl B(OH)₂ C-glycosylcompound 196 H Cl SH OH 197 H Cl SH D-glucitol 198 H Cl SH SO₃H 199 H ClSH PO₃H₂ 200 H Cl SH CHO 201 H Cl SH COOH 202 H Cl SH CH₂OH 203 H Cl SHsugar 204 H Cl SH C-glycosyl compound 205 H Cl OCH₃ OH 206 H Cl OCH₃D-glucitol 207 H Cl OCH₃ SO₃H 208 H Cl OCH₃ PO₃H₂ 209 H Cl OCH₃ CHO 210H Cl OCH₃ COOH 211 H Cl OCH₃ CH₂OH 212 H Cl OCH₃ sugar 213 H Cl OCH₃C-glycosyl compound 214 H CN H OH 215 H CN H D-glucitol 216 H CN H SO₃H217 H CN H PO₃H₂ 218 H CN H CHO 219 H CN H COOH 220 H CN H CH₂OH 221 HCN H sugar 222 H CN H C-glycosyl compound 223 H CN OH OH 224 H CN OHD-glucitol 225 H CN OH SO₃H 226 H CN OH PO₃H₂ 227 H CN OH CHO 228 H CNOH COOH 229 H CN OH CH₂OH 230 H CN OH sugar 231 H CN OH C-glycosylcompound 232 H CN CH₃ OH 233 H CN CH₃ D-glucitol 234 H CN CH₃ SO₃H 235 HCN CH₃ PO₃H₂ 236 H CN CH₃ CHO 237 H CN CH₃ COOH 238 H CN CH₃ CH₂OH 239 HCN CH₃ sugar 240 H CN CH₃ C-glycosyl compound 241 H CN Cl OH 242 H CN ClD-glucitol 243 H CN Cl SO₃H 244 H CN Cl PO₃H₂ 245 H CN Cl CHO 246 H CNCl COOH 247 H CN Cl CH₂OH 248 H CN Cl sugar 249 H CN Cl C-glycosylcompound 250 H CN B(OH)₂ OH 251 H CN B(OH)₂ D-glucitol 252 H CN B(OH)₂SO₃H 253 H CN B(OH)₂ PO₃H₂ 254 H CN B(OH)₂ CHO 255 H CN B(OH)₂ COOH 256H CN B(OH)₂ CH₂OH 257 H CN B(OH)₂ sugar 258 H CN B(OH)₂ C-glycosylcompound 259 H CN SH OH 260 H CN SH D-glucitol 261 H CN SH SO₃H 262 H CNSH PO₃H₂ 263 H CN SH CHO 264 H CN SH COOH 265 H CN SH CH₂OH 266 H CN SHsugar 267 H CN SH C-glycosyl compound 268 H CN OCH₃ OH 269 H CN OCH₃D-glucitol 270 H CN OCH₃ SO₃H 271 H CN OCH₃ PO₃H₂ 272 H CN OCH₃ CHO 273H CN OCH₃ COOH 274 H CN OCH₃ CH₂OH 275 H CN OCH₃ sugar 276 H CN OCH₃C-glycosyl compound 277 H CH₃ ^(a) H OH 278 H CH₃ ^(a) H D-glucitol 279H CH₃ ^(a) H SO₃H 280 H CH₃ ^(a) H PO₃H₂ 281 H CH₃ ^(a) H CHO 282 H CH₃^(a) H COOH 283 H CH₃ ^(a) H CH₂OH 284 H CH₃ ^(a) H sugar 285 H CH₃ ^(a)H C-glycosyl compound 286 H CH₃ ^(a) OH OH 287 H CH₃ ^(a) OH D-glucitol288 H CH₃ ^(a) OH SO₃H 289 H CH₃ ^(a) OH PO₃H₂ 290 H CH₃ ^(a) OH CHO 291H CH₃ ^(a) OH COOH 292 H CH₃ ^(a) OH CH₂OH 293 H CH₃ ^(a) OH sugar 294 HCH₃ ^(a) OH C-glycosyl compound 295 H CH₃ ^(a) CH₃ OH 296 H CH₃ ^(a) CH₃D-glucitol 297 H CH₃ ^(a) CH₃ SO₃H 298 H CH₃ ^(a) CH₃ PO₃H₂ 299 H CH₃^(a) CH₃ CHO 300 H CH₃ ^(a) CH₃ COOH 301 H CH₃ ^(a) CH₃ CH₂OH 302 H CH₃^(a) CH₃ sugar 303 H CH₃ ^(a) CH₃ C-glycosyl compound 304 H CH₃ ^(a) ClOH 305 H CH₃ ^(a) Cl D-glucitol 306 H CH₃ ^(a) Cl SO₃H 307 H CH₃ ^(a) ClPO₃H₂ 308 H CH₃ ^(a) Cl CHO 309 H CH₃ ^(a) Cl COOH 310 H CH₃ ^(a) ClCH₂OH 311 H CH₃ ^(a) Cl sugar 312 H CH₃ ^(a) Cl C-glycosyl compound 313H CH₃ ^(a) B(OH)₂ OH 314 H CH₃ ^(a) B(OH)₂ D-glucitol 315 H CH₃ ^(a)B(OH)₂ SO₃H 316 H CH₃ ^(a) B(OH)₂ PO₃H₂ 317 H CH₃ ^(a) B(OH)₂ CHO 318 HCH₃ ^(a) B(OH)₂ COOH 319 H CH₃ ^(a) B(OH)₂ CH₂OH 320 H CH₃ ^(a) B(OH)₂sugar 321 H CH₃ ^(a) B(OH)₂ C-glycosyl compound 322 H CH₃ ^(a) SH OH 323H CH₃ ^(a) SH D-glucitol 324 H CH₃ ^(a) SH SO₃H 325 H CH₃ ^(a) SH PO₃H₂326 H CH₃ ^(a) SH CHO 327 H CH₃ ^(a) SH COOH 328 H CH₃ ^(a) SH CH₂OH 329H CH₃ ^(a) SH sugar 330 H CH₃ ^(a) SH C-glycosyl compound 331 H CH₃ ^(a)OCH₃ OH 332 H CH₃ ^(a) OCH₃ D-glucitol 333 H CH₃ ^(a) OCH₃ SO₃H 334 HCH₃ ^(a) OCH₃ PO₃H₂ 335 H CH₃ ^(a) OCH₃ CHO 336 H CH₃ ^(a) OCH₃ COOH 337H CH₃ ^(a) OCH₃ CH₂OH 338 H CH₃ ^(a) OCH₃ sugar 339 H CH₃ ^(a) OCH₃C-glycosyl compound 340 H OCH3^(b) H OH 341 H OCH3^(b) H D-glucitol 342H OCH3^(b) H SO₃H 343 H OCH3^(b) H PO₃H₂ 344 H OCH3^(b) H CHO 345 HOCH3^(b) H COOH 346 H OCH3^(b) H CH₂OH 347 H OCH3^(b) H sugar 348 HOCH3^(b) H C-glycosyl compound 349 H OCH3^(b) OH OH 350 H OCH3^(b) OHD-glucitol 351 H OCH3^(b) OH SO₃H 352 H OCH3^(b) OH PO₃H₂ 353 H OCH3^(b)OH CHO 354 H OCH3^(b) OH COOH 355 H OCH3^(b) OH CH₂OH 356 H OCH3^(b) OHsugar 357 H OCH3^(b) OH C-glycosyl compound 358 H OCH3^(b) CH₃ OH 359 HOCH3^(b) CH₃ D-glucitol 360 H OCH3^(b) CH₃ SO₃H 361 H OCH3^(b) CH₃ PO₃H₂362 H OCH3^(b) CH₃ CHO 363 H OCH3^(b) CH₃ COOH 364 H OCH3^(b) CH₃ CH₂OH365 H OCH3^(b) CH₃ sugar 366 H OCH3^(b) CH₃ C-glycosyl compound 367 HOCH3^(b) Cl OH 368 H OCH3^(b) Cl D-glucitol 369 H OCH3^(b) Cl SO₃H 370 HOCH3^(b) Cl PO₃H₂ 371 H OCH3^(b) Cl CHO 372 H OCH3^(b) Cl COOH 373 HOCH3^(b) Cl CH₂OH 374 H OCH3^(b) Cl sugar 375 H OCH3^(b) Cl C-glycosylcompound 376 H OCH3^(b) B(OH)₂ OH 377 H OCH3^(b) B(OH)₂ D-glucitol 378 HOCH3^(b) B(OH)₂ SO₃H 379 H OCH3^(b) B(OH)₂ PO₃H₂ 380 H OCH3^(b) B(OH)₂CHO 381 H OCH3^(b) B(OH)₂ COOH 382 H OCH3^(b) B(OH)₂ CH₂OH 383 HOCH3^(b) B(OH)₂ sugar 384 H OCH3^(b) B(OH)₂ C-glycosyl compound 385 HOCH3^(b) SH OH 386 H OCH3^(b) SH D-glucitol 387 H OCH3^(b) SH SO₃H 388 HOCH3^(b) SH PO₃H₂ 389 H OCH3^(b) SH CHO 390 H OCH3^(b) SH COOH 391 HOCH3^(b) SH CH₂OH 392 H OCH3^(b) SH sugar 393 H OCH3^(b) SH C-glycosylcompound 394 H OCH3^(b) OCH₃ OH 395 H OCH3^(b) OCH₃ D-glucitol 396 HOCH3^(b) OCH₃ SO₃H 397 H OCH3^(b) OCH₃ PO₃H₂ 398 H OCH3^(b) OCH₃ CHO 399H OCH3^(b) OCH₃ COOH 400 H OCH3^(b) OCH₃ CH₂OH 401 H OCH3^(b) OCH₃ sugar402 H OCH3^(b) OCH₃ C-glycosyl compound 403 F H H OH 404 F H HD-glucitol 405 F H H SO₃H 406 F H H PO₃H₂ 407 F H H CHO 408 F H H COOH409 F H H CH₂OH 410 F H H sugar 411 F H H C-glycosyl compound 412 F H OHCHO 413 F H OH COOH 414 F H OH CH₂OH 415 F H OH sugar 416 F H OHC-glycosyl compound 417 F H CH₃ OH 418 F H CH₃ D-glucitol 419 F H CH₃SO₃H 420 F H CH₃ PO₃H₂ 421 F H CH₃ CHO 422 F H CH₃ COOH 423 F H CH₃CH₂OH 424 F H CH₃ sugar 425 F H CH₃ C-glycosyl compound 426 F H Cl OH427 F H Cl D-glucitol 428 F H Cl SO₃H 429 F H Cl PO₃H₂ 430 F H Cl CHO431 F H Cl COOH 432 F H Cl CH₂OH 433 F H Cl sugar 434 F H Cl C-glycosylcompound 435 F H B(OH)₂ OH 436 F H B(OH)₂ D-glucitol 437 F H B(OH)₂ SO₃H438 F H B(OH)₂ PO₃H₂ 439 F H B(OH)₂ CHO 440 F H B(OH)₂ COOH 441 F HB(OH)₂ CH₂OH 442 F H B(OH)₂ sugar 443 F H B(OH)₂ C-glycosyl compound 444F H SH OH 445 F H SH D-glucitol 446 F H SH SO₃H 447 F H SH PO₃H₂ 448 F HSH CHO 449 F H SH COOH 450 F H SH CH₂OH 451 F H SH sugar 452 F H SHC-glycosyl compound 453 F H OCH₃ OH 454 F H OCH₃ D-glucitol 455 F H OCH₃SO₃H 456 F H OCH₃ PO₃H₂ 457 F H OCH₃ CHO 458 F H OCH₃ COOH 459 F H OCH₃CH₂OH 460 F H OCH₃ sugar 461 F H OCH₃ C-glycosyl compound 462 F F H OH463 F F H D-glucitol 464 F F H SO₃H 465 F F H PO₃H₂ 466 F F H CHO 467 FF H COOH 468 F F H CH₂OH 469 F F H sugar 470 F F H C-glycosyl compound471 F F OH CHO 472 F F OH COOH 473 F F OH CH₂OH 474 F F OH sugar 475 F FOH C-glycosyl compound 476 F F CH₃ OH 477 F F CH₃ D-glucitol 478 F F CH₃SO₃H 479 F F CH₃ PO₃H₂ 480 F F CH₃ CHO 481 F F CH₃ COOH 482 F F CH₃CH₂OH 483 F F CH₃ sugar 484 F F CH₃ C-glycosyl compound 485 F F Cl OH486 F F Cl D-glucitol 487 F F Cl SO₃H 488 F F Cl PO₃H₂ 489 F F Cl CHO490 F F Cl COOH 491 F F Cl CH₂OH 492 F F Cl sugar 493 F F Cl C-glycosylcompound 494 F F B(OH)₂ OH 495 F F B(OH)₂ D-glucitol 496 F F B(OH)₂ SO₃H497 F F B(OH)₂ PO₃H₂ 498 F F B(OH)₂ CHO 499 F F B(OH)₂ COOH 500 F FB(OH)₂ CH₂OH 501 F F B(OH)₂ sugar 502 F F B(OH)₂ C-glycosyl compound 503F F SH OH 504 F F SH D-glucitol 505 F F SH SO₃H 506 F F SH PO₃H₂ 507 F FSH CHO 508 F F SH COOH 509 F F SH CH₂OH 510 F F SH sugar 511 F F SHC-glycosyl compound 512 F F OCH₃ OH 513 F F OCH₃ D-glucitol 514 F F OCH₃SO₃H 515 F F OCH₃ PO₃H₂ 516 F F OCH₃ CHO 517 F F OCH₃ COOH 518 F F OCH₃CH₂OH 519 F F OCH₃ sugar 520 F F OCH₃ C-glycosyl compound 521 F Cl H OH522 F Cl H D-glucitol 523 F Cl H SO₃H 524 F Cl H PO₃H₂ 525 F Cl H CHO526 F Cl H COOH 527 F Cl H CH₂OH 528 F Cl H sugar 529 F Cl H C-glycosylcompound 530 F Cl OH CHO 531 F Cl OH COOH 532 F Cl OH CH₂OH 533 F Cl OHsugar 534 F Cl OH C-glycosyl compound 535 F Cl CH₃ OH 536 F Cl CH₃D-glucitol 537 F Cl CH₃ SO₃H 538 F Cl CH₃ PO₃H₂ 539 F Cl CH₃ CHO 540 FCl CH₃ COOH 541 F Cl CH₃ CH₂OH 542 F Cl CH₃ sugar 543 F Cl CH₃C-glycosyl compound 544 F Cl Cl OH 545 F Cl Cl D-glucitol 546 F Cl ClSO₃H 547 F Cl Cl PO₃H₂ 548 F Cl Cl CHO 549 F Cl Cl COOH 550 F Cl ClCH₂OH 551 F Cl Cl sugar 552 F Cl Cl C-glycosyl compound 553 F Cl B(OH)₂OH 554 F Cl B(OH)₂ D-glucitol 555 F Cl B(OH)₂ SO₃H 556 F Cl B(OH)₂ PO₃H₂557 F Cl B(OH)₂ CHO 558 F Cl B(OH)₂ COOH 559 F Cl B(OH)₂ CH₂OH 560 F ClB(OH)₂ sugar 561 F Cl B(OH)₂ C-glycosyl compound 562 F Cl SH OH 563 F ClSH D-glucitol 564 F Cl SH SO₃H 565 F Cl SH PO₃H₂ 566 F Cl SH CHO 567 FCl SH COOH 568 F Cl SH CH₂OH 569 F Cl SH sugar 570 F Cl SH C-glycosylcompound 571 F Cl OCH₃ OH 572 F Cl OCH₃ D-glucitol 573 F Cl OCH₃ SO₃H574 F Cl OCH₃ PO₃H₂ 575 F Cl OCH₃ CHO 576 F Cl OCH₃ COOH 577 F Cl OCH₃CH₂OH 578 F Cl OCH₃ sugar 579 F Cl OCH₃ C-glycosyl compound 580 F CN HOH 581 F CN H D-glucitol 582 F CN H SO₃H 583 F CN H PO₃H₂ 584 F CN H CHO585 F CN H COOH 586 F CN H CH₂OH 587 F CN H sugar 588 F CN H C-glycosylcompound 589 F CN OH OH 590 F CN OH D-glucitol 591 F CN OH SO₃H 592 F CNOH PO₃H₂ 593 F CN OH CHO 594 F CN OH COOH 595 F CN OH CH₂OH 596 F CN OHsugar 597 F CN OH C-glycosyl compound 598 F CN CH₃ OH 599 F CN CH₃D-glucitol 600 F CN CH₃ SO₃H 601 F CN CH₃ PO₃H₂ 602 F CN CH₃ CHO 603 FCN CH₃ COOH 604 F CN CH₃ CH₂OH 605 F CN CH₃ sugar 606 F CN CH₃C-glycosyl compound 607 F CN Cl OH 608 F CN Cl D-glucitol 609 F CN ClSO₃H 610 F CN Cl PO₃H₂ 611 F CN Cl CHO 612 F CN Cl COOH 613 F CN ClCH₂OH 614 F CN Cl sugar 615 F CN Cl C-glycosyl compound 616 F CN B(OH)₂OH 617 F CN B(OH)₂ D-glucitol 618 F CN B(OH)₂ SO₃H 619 F CN B(OH)₂ PO₃H₂620 F CN B(OH)₂ CHO 621 F CN B(OH)₂ COOH 622 F CN B(OH)₂ CH₂OH 623 F CNB(OH)₂ sugar 624 F CN B(OH)₂ C-glycosyl compound 625 F CN SH OH 626 F CNSH D-glucitol 627 F CN SH SO₃H 628 F CN SH PO₃H₂ 629 F CN SH CHO 630 FCN SH COOH 631 F CN SH CH₂OH 632 F CN SH sugar 633 F CN SH C-glycosylcompound 634 F CN OCH₃ OH 635 F CN OCH₃ D-glucitol 636 F CN OCH₃ SO₃H637 F CN OCH₃ PO₃H₂ 638 F CN OCH₃ CHO 639 F CN OCH₃ COOH 640 F CN OCH₃CH₂OH 641 F CN OCH₃ sugar 642 F CN OCH₃ C-glycosyl compound 643 F CH₃^(a) H OH 644 F CH₃ ^(a) H D-glucitol 645 F CH₃ ^(a) H SO₃H 646 F CH₃^(a) H PO₃H₂ 647 F CH₃ ^(a) H CHO 648 F CH₃ ^(a) H COOH 649 F CH₃ ^(a) HCH₂OH 650 F CH₃ ^(a) H sugar 651 F CH₃ ^(a) H C-glycosyl compound 652 FCH₃ ^(a) OH OH 653 F CH₃ ^(a) OH D-glucitol 654 F CH₃ ^(a) OH SO₃H 655 FCH₃ ^(a) OH PO₃H₂ 656 F CH₃ ^(a) OH CHO 657 F CH₃ ^(a) OH COOH 658 F CH₃^(a) OH CH₂OH 659 F CH₃ ^(a) OH sugar 660 F CH₃ ^(a) OH C-glycosylcompound 661 F CH₃ ^(a) CH₃ OH 662 F CH₃ ^(a) CH₃ D-glucitol 663 F CH₃^(a) CH₃ SO₃H 664 F CH₃ ^(a) CH₃ PO₃H₂ 665 F CH₃ ^(a) CH₃ CHO 666 F CH₃^(a) CH₃ COOH 667 F CH₃ ^(a) CH₃ CH₂OH 668 F CH₃ ^(a) CH₃ sugar 669 FCH₃ ^(a) CH₃ C-glycosyl compound 670 F CH₃ ^(a) Cl OH 671 F CH₃ ^(a) ClD-glucitol 672 F CH₃ ^(a) Cl SO₃H 673 F CH₃ ^(a) Cl PO₃H₂ 674 F CH₃ ^(a)Cl CHO 675 F CH₃ ^(a) Cl COOH 676 F CH₃ ^(a) Cl CH₂OH 677 F CH₃ ^(a) Clsugar 678 F CH₃ ^(a) Cl C-glycosyl compound 679 F CH₃ ^(a) B(OH)₂ OH 680F CH₃ ^(a) B(OH)₂ D-glucitol 681 F CH₃ ^(a) B(OH)₂ SO₃H 682 F CH₃ ^(a)B(OH)₂ PO₃H₂ 683 F CH₃ ^(a) B(OH)₂ CHO 684 F CH₃ ^(a) B(OH)₂ COOH 685 FCH₃ ^(a) B(OH)₂ CH₂OH 686 F CH₃ ^(a) B(OH)₂ sugar 687 F CH₃ ^(a) B(OH)₂C-glycosyl compound 688 F CH₃ ^(a) SH OH 689 F CH₃ ^(a) SH D-glucitol690 F CH₃ ^(a) SH SO₃H 691 F CH₃ ^(a) SH PO₃H₂ 692 F CH₃ ^(a) SH CHO 693F CH₃ ^(a) SH COOH 694 F CH₃ ^(a) SH CH₂OH 695 F CH₃ ^(a) SH sugar 696 FCH₃ ^(a) SH C-glycosyl compound 697 F CH₃ ^(a) OCH₃ OH 698 F CH₃ ^(a)OCH₃ D-glucitol 699 F CH₃ ^(a) OCH₃ SO₃H 700 F CH₃ ^(a) OCH₃ PO₃H₂ 701 FCH₃ ^(a) OCH₃ CHO 702 F CH₃ ^(a) OCH₃ COOH 703 F CH₃ ^(a) OCH₃ CH₂OH 704F CH₃ ^(a) OCH₃ sugar 705 F CH₃ ^(a) OCH₃ C-glycosyl compound 706 FOCH3^(b) H OH 707 F OCH3^(b) H D-glucitol 708 F OCH3^(b) H SO₃H 709 FOCH3^(b) H PO₃H₂ 710 F OCH3^(b) H CHO 711 F OCH3^(b) H COOH 712 FOCH3^(b) H CH₂OH 713 F OCH3^(b) H sugar 714 F OCH3^(b) H C-glycosylcompound 715 F OCH3^(b) OH OH 716 F OCH3^(b) OH D-glucitol 717 FOCH3^(b) OH SO₃H 718 F OCH3^(b) OH PO₃H₂ 719 F OCH3^(b) OH CHO 720 FOCH3^(b) OH COOH 721 F OCH3^(b) OH CH₂OH 722 F OCH3^(b) OH sugar 723 FOCH3^(b) OH C-glycosyl compound 724 F OCH3^(b) CH₃ OH 725 F OCH3^(b) CH₃D-glucitol 726 F OCH3^(b) CH₃ SO₃H 727 F OCH3^(b) CH₃ PO₃H₂ 728 FOCH3^(b) CH₃ CHO 729 F OCH3^(b) CH₃ COOH 730 F OCH3^(b) CH₃ CH₂OH 731 FOCH3^(b) CH₃ sugar 732 F OCH3^(b) CH₃ C-glycosyl compound 733 F OCH3^(b)Cl OH 734 F OCH3^(b) Cl D-glucitol 735 F OCH3^(b) Cl SO₃H 736 F OCH3^(b)Cl PO₃H₂ 737 F OCH3^(b) Cl CHO 738 F OCH3^(b) Cl COOH 739 F OCH3^(b) ClCH₂OH 740 F OCH3^(b) Cl sugar 741 F OCH3^(b) Cl C-glycosyl compound 742F OCH3^(b) B(OH)₂ OH 743 F OCH3^(b) B(OH)₂ D-glucitol 744 F OCH3^(b)B(OH)₂ SO₃H 745 F OCH3^(b) B(OH)₂ PO₃H₂ 746 F OCH3^(b) B(OH)₂ CHO 747 FOCH3^(b) B(OH)₂ COOH 748 F OCH3^(b) B(OH)₂ CH₂OH 749 F OCH3^(b) B(OH)₂sugar 750 F OCH3^(b) B(OH)₂ C-glycosyl compound 751 F OCH3^(b) SH OH 752F OCH3^(b) SH D-glucitol 753 F OCH3^(b) SH SO₃H 754 F OCH3^(b) SH PO₃H₂755 F OCH3^(b) SH CHO 756 F OCH3^(b) SH COOH 757 F OCH3^(b) SH CH₂OH 758F OCH3^(b) SH sugar 759 F OCH3^(b) SH C-glycosyl compound 760 F OCH3^(b)OCH₃ OH 761 F OCH3^(b) OCH₃ D-glucitol 762 F OCH3^(b) OCH₃ SO₃H 763 FOCH3^(b) OCH₃ PO₃H₂ 764 F OCH3^(b) OCH₃ CHO 765 F OCH3^(b) OCH₃ COOH 766F OCH3^(b) OCH₃ CH₂OH 767 F OCH3^(b) OCH₃ sugar 768 F OCH3^(b) OCH₃C-glycosyl compound 769 Cl H H OH 770 Cl H H D-glucitol 771 Cl H H SO₃H772 Cl H H PO₃H₂ 773 Cl H H CHO 774 Cl H H COOH 775 Cl H H CH₂OH 776 ClH H sugar 777 Cl H H C-glycosyl compound 778 Cl H OH CHO 779 Cl H OHCOOH 780 Cl H OH CH₂OH 781 Cl H OH sugar 782 Cl H OH C-glycosyl compound783 Cl H CH₃ OH 784 Cl H CH₃ D-glucitol 785 Cl H CH₃ SO₃H 786 Cl H CH₃PO₃H₂ 787 Cl H CH₃ CHO 788 Cl H CH₃ COOH 789 Cl H CH₃ CH₂OH 790 Cl H CH₃sugar 791 Cl H CH₃ C-glycosyl compound 792 Cl H Cl OH 793 Cl H ClD-glucitol 794 Cl H Cl SO₃H 795 Cl H Cl PO₃H₂ 796 Cl H Cl CHO 797 Cl HCl COOH 798 Cl H Cl CH₂OH 799 Cl H Cl sugar 800 Cl H Cl C-glycosylcompound 801 Cl H B(OH)₂ OH 802 Cl H B(OH)₂ D-glucitol 803 Cl H B(OH)₂SO₃H 804 Cl H B(OH)₂ PO₃H₂ 805 Cl H B(OH)₂ CHO 806 Cl H B(OH)₂ COOH 807Cl H B(OH)₂ CH₂OH 808 Cl H B(OH)₂ sugar 809 Cl H B(OH)₂ C-glycosylcompound 810 Cl H SH OH 811 Cl H SH D-glucitol 812 Cl H SH SO₃H 813 Cl HSH PO₃H₂ 814 Cl H SH CHO 815 Cl H SH COOH 816 Cl H SH CH₂OH 817 Cl H SHsugar 818 Cl H SH C-glycosyl compound 819 Cl H OCH₃ OH 820 Cl H OCH₃D-glucitol 821 Cl H OCH₃ SO₃H 822 Cl H OCH₃ PO₃H₂ 823 Cl H OCH₃ CHO 824Cl H OCH₃ COOH 825 Cl H OCH₃ CH₂OH 826 Cl H OCH₃ sugar 827 Cl H OCH₃C-glycosyl compound 828 Cl F H OH 829 Cl F H D-glucitol 830 Cl F H SO₃H831 Cl F H PO₃H₂ 832 Cl F H CHO 833 Cl F H COOH 834 Cl F H CH₂OH 835 ClF H sugar 836 Cl F H C-glycosyl compound 837 Cl F OH CHO 838 Cl F OHCOOH 839 Cl F OH CH₂OH 840 Cl F OH sugar 841 Cl F OH C-glycosyl compound842 Cl F CH₃ OH 843 Cl F CH₃ D-glucitol 844 Cl F CH₃ SO₃H 845 Cl F CH₃PO₃H₂ 846 Cl F CH₃ CHO 847 Cl F CH₃ COOH 848 Cl F CH₃ CH₂OH 849 Cl F CH₃sugar 850 Cl F CH₃ C-glycosyl compound 851 Cl F Cl OH 852 Cl F ClD-glucitol 853 Cl F Cl SO₃H 854 Cl F Cl PO₃H₂ 855 Cl F Cl CHO 856 Cl FCl COOH 857 Cl F Cl CH₂OH 858 Cl F Cl sugar 859 Cl F Cl C-glycosylcompound 860 Cl F B(OH)₂ OH 861 Cl F B(OH)₂ D-glucitol 862 Cl F B(OH)₂SO₃H 863 Cl F B(OH)₂ PO₃H₂ 864 Cl F B(OH)₂ CHO 865 Cl F B(OH)₂ COOH 866Cl F B(OH)₂ CH₂OH 867 Cl F B(OH)₂ sugar 868 Cl F B(OH)₂ C-glycosylcompound 869 Cl F SH OH 870 Cl F SH D-glucitol 871 Cl F SH SO₃H 872 Cl FSH PO₃H₂ 873 Cl F SH CHO 874 Cl F SH COOH 875 Cl F SH CH₂OH 876 Cl F SHsugar 877 Cl F SH C-glycosyl compound 878 Cl F OCH₃ OH 879 Cl F OCH₃D-glucitol 880 Cl F OCH₃ SO₃H 881 Cl F OCH₃ PO₃H₂ 882 Cl F OCH₃ CHO 883Cl F OCH₃ COOH 884 Cl F OCH₃ CH₂OH 885 Cl F OCH₃ sugar 886 Cl F OCH₃C-glycosyl compound 887 Cl Cl H OH 888 Cl Cl H D-glucitol 889 Cl Cl HSO₃H 890 Cl Cl H PO₃H₂ 891 Cl Cl H CHO 892 Cl Cl H COOH 893 Cl Cl HCH₂OH 894 Cl Cl H sugar 895 Cl Cl H C-glycosyl compound 896 Cl Cl OH CHO897 Cl Cl OH COOH 898 Cl Cl OH CH₂OH 899 Cl Cl OH sugar 900 Cl Cl OHC-glycosyl compound 901 Cl Cl CH₃ OH 902 Cl Cl CH₃ D-glucitol 903 Cl ClCH₃ SO₃H 904 Cl Cl CH₃ PO₃H₂ 905 Cl Cl CH₃ CHO 906 Cl Cl CH₃ COOH 907 ClCl CH₃ CH₂OH 908 Cl Cl CH₃ sugar 909 Cl Cl CH₃ C-glycosyl compound 910Cl Cl Cl OH 911 Cl Cl Cl D-glucitol 912 Cl Cl Cl SO₃H 913 Cl Cl Cl PO₃H₂914 Cl Cl Cl CHO 915 Cl Cl Cl COOH 916 Cl Cl Cl CH₂OH 917 Cl Cl Cl sugar918 Cl Cl Cl C-glycosyl compound 919 Cl Cl B(OH)₂ OH 920 Cl Cl B(OH)₂D-glucitol 921 Cl Cl B(OH)₂ SO₃H 922 Cl Cl B(OH)₂ PO₃H₂ 923 Cl Cl B(OH)₂CHO 924 Cl Cl B(OH)₂ COOH 925 Cl Cl B(OH)₂ CH₂OH 926 Cl Cl B(OH)₂ sugar927 Cl Cl B(OH)₂ C-glycosyl compound 928 Cl Cl SH OH 929 Cl Cl SHD-glucitol 930 Cl Cl SH SO₃H 931 Cl Cl SH PO₃H₂ 932 Cl Cl SH CHO 933 ClCl SH COOH 934 Cl Cl SH CH₂OH 935 Cl Cl SH sugar 936 Cl Cl SH C-glycosylcompound 937 Cl Cl OCH₃ OH 938 Cl Cl OCH₃ D-glucitol 939 Cl Cl OCH₃ SO₃H940 Cl Cl OCH₃ PO₃H₂ 941 Cl Cl OCH₃ CHO 942 Cl Cl OCH₃ COOH 943 Cl ClOCH₃ CH₂OH 944 Cl Cl OCH₃ sugar 945 Cl Cl OCH₃ C-glycosyl compound 946Cl CN H OH 947 Cl CN H D-glucitol 948 Cl CN H SO₃H 949 Cl CN H PO₃H₂ 950Cl CN H CHO 951 Cl CN H COOH 952 Cl CN H CH₂OH 953 Cl CN H sugar 954 ClCN H C-glycosyl compound 955 Cl CN OH OH 956 Cl CN OH D-glucitol 957 ClCN OH SO₃H 958 Cl CN OH PO₃H₂ 959 Cl CN OH CHO 960 Cl CN OH COOH 961 ClCN OH CH₂OH 962 Cl CN OH sugar 963 Cl CN OH C-glycosyl compound 964 ClCN CH₃ OH 965 Cl CN CH₃ D-glucitol 966 Cl CN CH₃ SO₃H 967 Cl CN CH₃PO₃H₂ 968 Cl CN CH₃ CHO 969 Cl CN CH₃ COOH 970 Cl CN CH₃ CH₂OH 971 Cl CNCH₃ sugar 972 Cl CN CH₃ C-glycosyl compound 973 Cl CN Cl OH 974 Cl CN ClD-glucitol 975 Cl CN Cl SO₃H 976 Cl CN Cl PO₃H₂ 977 Cl CN Cl CHO 978 ClCN Cl COOH 979 Cl CN Cl CH₂OH 980 Cl CN Cl sugar 981 Cl CN Cl C-glycosylcompound 982 Cl CN B(OH)₂ OH 983 Cl CN B(OH)₂ D-glucitol 984 Cl CNB(OH)₂ SO₃H 985 Cl CN B(OH)₂ PO₃H₂ 986 Cl CN B(OH)₂ CHO 987 Cl CN B(OH)₂COOH 988 Cl CN B(OH)₂ CH₂OH 989 Cl CN B(OH)₂ sugar 990 Cl CN B(OH)₂C-glycosyl compound 991 Cl CN SH OH 992 Cl CN SH D-glucitol 993 Cl CN SHSO₃H 994 Cl CN SH PO₃H₂ 995 Cl CN SH CHO 996 Cl CN SH COOH 997 Cl CN SHCH₂OH 998 Cl CN SH sugar 999 Cl CN SH C-glycosyl compound 1000 Cl CNOCH₃ OH 1001 Cl CN OCH₃ D-glucitol 1002 Cl CN OCH₃ SO₃H 1003 Cl CN OCH₃PO₃H₂ 1004 Cl CN OCH₃ CHO 1005 Cl CN OCH₃ COOH 1006 Cl CN OCH₃ CH₂OH1007 Cl CN OCH₃ sugar 1008 Cl CN OCH₃ C-glycosyl compound 1009 Cl CH₃^(a) H OH 1010 Cl CH₃ ^(a) H D-glucitol 1011 Cl CH₃ ^(a) H SO₃H 1012 ClCH₃ ^(a) H PO₃H₂ 1013 Cl CH₃ ^(a) H CHO 1014 Cl CH₃ ^(a) H COOH 1015 ClCH₃ ^(a) H CH₂OH 1016 Cl CH₃ ^(a) H sugar 1017 Cl CH₃ ^(a) H C-glycosylcompound 1018 Cl CH₃ ^(a) OH OH 1019 Cl CH₃ ^(a) OH D-glucitol 1020 ClCH₃ ^(a) OH SO₃H 1021 Cl CH₃ ^(a) OH PO₃H₂ 1022 Cl CH₃ ^(a) OH CHO 1023Cl CH₃ ^(a) OH COOH 1024 Cl CH₃ ^(a) OH CH₂OH 1025 Cl CH₃ ^(a) OH sugar1026 Cl CH₃ ^(a) OH C-glycosyl compound 1027 Cl CH₃ ^(a) CH₃ OH 1028 ClCH₃ ^(a) CH₃ D-glucitol 1029 Cl CH₃ ^(a) CH₃ SO₃H 1030 Cl CH₃ ^(a) CH₃PO₃H₂ 1031 Cl CH₃ ^(a) CH₃ CHO 1032 Cl CH₃ ^(a) CH₃ COOH 1033 Cl CH₃^(a) CH₃ CH₂OH 1034 Cl CH₃ ^(a) CH₃ sugar 1035 Cl CH₃ ^(a) CH₃C-glycosyl compound 1036 Cl CH₃ ^(a) Cl OH 1037 Cl CH₃ ^(a) ClD-glucitol 1038 Cl CH₃ ^(a) Cl SO₃H 1039 Cl CH₃ ^(a) Cl PO₃H₂ 1040 ClCH₃ ^(a) Cl CHO 1041 Cl CH₃ ^(a) Cl COOH 1042 Cl CH₃ ^(a) Cl CH₂OH 1043Cl CH₃ ^(a) Cl sugar 1044 Cl CH₃ ^(a) Cl C-glycosyl compound 1045 Cl CH₃^(a) B(OH)₂ OH 1046 Cl CH₃ ^(a) B(OH)₂ D-glucitol 1047 Cl CH₃ ^(a)B(OH)₂ SO₃H 1048 Cl CH₃ ^(a) B(OH)₂ PO₃H₂ 1049 Cl CH₃ ^(a) B(OH)₂ CHO1050 Cl CH₃ ^(a) B(OH)₂ COOH 1051 Cl CH₃ ^(a) B(OH)₂ CH₂OH 1052 Cl CH₃^(a) B(OH)₂ sugar 1053 Cl CH₃ ^(a) B(OH)₂ C-glycosyl compound 1054 ClCH₃ ^(a) SH OH 1055 Cl CH₃ ^(a) SH D-glucitol 1056 Cl CH₃ ^(a) SH SO₃H1057 Cl CH₃ ^(a) SH PO₃H₂ 1058 Cl CH₃ ^(a) SH CHO 1059 Cl CH₃ ^(a) SHCOOH 1060 Cl CH₃ ^(a) SH CH₂OH 1061 Cl CH₃ ^(a) SH sugar 1062 Cl CH₃^(a) SH C-glycosyl compound 1063 Cl CH₃ ^(a) OCH₃ OH 1064 Cl CH₃ ^(a)OCH₃ D-glucitol 1065 Cl CH₃ ^(a) OCH₃ SO₃H 1066 Cl CH₃ ^(a) OCH₃ PO₃H₂1067 Cl CH₃ ^(a) OCH₃ CHO 1068 Cl CH₃ ^(a) OCH₃ COOH 1069 Cl CH₃ ^(a)OCH₃ CH₂OH 1070 Cl CH₃ ^(a) OCH₃ sugar 1071 Cl CH₃ ^(a) OCH₃ C-glycosylcompound 1072 Cl OCH3^(b) H OH 1073 Cl OCH3^(b) H D-glucitol 1074 ClOCH3^(b) H SO₃H 1075 Cl OCH3^(b) H PO₃H₂ 1076 Cl OCH3^(b) H CHO 1077 ClOCH3^(b) H COOH 1078 Cl OCH3^(b) H CH₂OH 1079 Cl OCH3^(b) H sugar 1080Cl OCH3^(b) H C-glycosyl compound 1081 Cl OCH3^(b) OH OH 1082 ClOCH3^(b) OH D-glucitol 1083 Cl OCH3^(b) OH SO₃H 1084 Cl OCH3^(b) OHPO₃H₂ 1085 Cl OCH3^(b) OH CHO 1086 Cl OCH3^(b) OH COOH 1087 Cl OCH3^(b)OH CH₂OH 1088 Cl OCH3^(b) OH sugar 1089 Cl OCH3^(b) OH C-glycosylcompound 1090 Cl OCH3^(b) CH₃ OH 1091 Cl OCH3^(b) CH₃ D-glucitol 1092 ClOCH3^(b) CH₃ SO₃H 1093 Cl OCH3^(b) CH₃ PO₃H₂ 1094 Cl OCH3^(b) CH₃ CHO1095 Cl OCH3^(b) CH₃ COOH 1096 Cl OCH3^(b) CH₃ CH₂OH 1097 Cl OCH3^(b)CH₃ sugar 1098 Cl OCH3^(b) CH₃ C-glycosyl compound 1099 Cl OCH3^(b) ClOH 1100 Cl OCH3^(b) Cl D-glucitol 1101 Cl OCH3^(b) Cl SO₃H 1102 ClOCH3^(b) Cl PO₃H₂ 1103 Cl OCH3^(b) Cl CHO 1104 Cl OCH3^(b) Cl COOH 1105Cl OCH3^(b) Cl CH₂OH 1106 Cl OCH3^(b) Cl sugar 1107 Cl OCH3^(b) ClC-glycosyl compound 1108 Cl OCH3^(b) B(OH)₂ OH 1109 Cl OCH3^(b) B(OH)₂D-glucitol 1110 Cl OCH3^(b) B(OH)₂ SO₃H 1111 Cl OCH3^(b) B(OH)₂ PO₃H₂1112 Cl OCH3^(b) B(OH)₂ CHO 1113 Cl OCH3^(b) B(OH)₂ COOH 1114 ClOCH3^(b) B(OH)₂ CH₂OH 1115 Cl OCH3^(b) B(OH)₂ sugar 1116 Cl OCH3^(b)B(OH)₂ C-glycosyl compound 1117 Cl OCH3^(b) SH OH 1118 Cl OCH3^(b) SHD-glucitol 1119 Cl OCH3^(b) SH SO₃H 1120 Cl OCH3^(b) SH PO₃H₂ 1121 ClOCH3^(b) SH CHO 1122 Cl OCH3^(b) SH COOH 1123 Cl OCH3^(b) SH CH₂OH 1124Cl OCH3^(b) SH sugar 1125 Cl OCH3^(b) SH C-glycosyl compound 1126 ClOCH3^(b) OCH₃ OH 1127 Cl OCH3^(b) OCH₃ D-glucitol 1128 Cl OCH3^(b) OCH₃SO₃H 1129 Cl OCH3^(b) OCH₃ PO₃H₂ 1130 Cl OCH3^(b) OCH₃ CHO 1131 ClOCH3^(b) OCH₃ COOH 1132 Cl OCH3^(b) OCH₃ CH₂OH 1133 Cl OCH3^(b) OCH₃sugar 1134 Cl OCH3^(b) OCH₃ C-glycosyl compound 1135 CN H H OH 1136 CN HH D-glucitol 1137 CN H H SO₃H 1138 CN H H PO₃H₂ 1139 CN H H CHO 1140 CNH H COOH 1141 CN H H CH₂OH 1142 CN H H sugar 1143 CN H H C-glycosylcompound 1144 CN H OH OH 1145 CN H OH D-glucitol 1146 CN H OH SO₃H 1147CN H OH PO₃H₂ 1148 CN H OH CHO 1149 CN H OH COOH 1150 CN H OH CH₂OH 1151CN H OH sugar 1152 CN H OH C-glycosyl compound 1153 CN H CH₃ OH 1154 CNH CH₃ D-glucitol 1155 CN H CH₃ SO₃H 1156 CN H CH₃ PO₃H₂ 1157 CN H CH₃CHO 1158 CN H CH₃ COOH 1159 CN H CH₃ CH₂OH 1160 CN H CH₃ sugar 1161 CN HCH₃ C-glycosyl compound 1162 CN H Cl OH 1163 CN H Cl D-glucitol 1164 CNH Cl SO₃H 1165 CN H Cl PO₃H₂ 1166 CN H Cl CHO 1167 CN H Cl COOH 1168 CNH Cl CH₂OH 1169 CN H Cl sugar 1170 CN H Cl C-glycosyl compound 1171 CN HB(OH)₂ OH 1172 CN H B(OH)₂ D-glucitol 1173 CN H B(OH)₂ SO₃H 1174 CN HB(OH)₂ PO₃H₂ 1175 CN H B(OH)₂ CHO 1176 CN H B(OH)₂ COOH 1177 CN H B(OH)₂CH₂OH 1178 CN H B(OH)₂ sugar 1179 CN H B(OH)₂ C-glycosyl compound 1180CN H SH OH 1181 CN H SH D-glucitol 1182 CN H SH SO₃H 1183 CN H SH PO₃H₂1184 CN H SH CHO 1185 CN H SH COOH 1186 CN H SH CH₂OH 1187 CN H SH sugar1188 CN H SH C-glycosyl compound 1189 CN H OCH₃ OH 1190 CN H OCH₃D-glucitol 1191 CN H OCH₃ SO₃H 1192 CN H OCH₃ PO₃H₂ 1193 CN H OCH₃ CHO1194 CN H OCH₃ COOH 1195 CN H OCH₃ CH₂OH 1196 CN H OCH₃ sugar 1197 CN HOCH₃ C-glycosyl compound 1198 CN F H OH 1199 CN F H D-glucitol 1200 CN FH SO₃H 1201 CN F H PO₃H₂ 1202 CN F H CHO 1203 CN F H COOH 1204 CN F HCH₂OH 1205 CN F H sugar 1206 CN F H C-glycosyl compound 1207 CN F OH OH1208 CN F OH D-glucitol 1209 CN F OH SO₃H 1210 CN F OH PO₃H₂ 1211 CN FOH CHO 1212 CN F OH COOH 1213 CN F OH CH₂OH 1214 CN F OH sugar 1215 CN FOH C-glycosyl compound 1216 CN F CH₃ OH 1217 CN F CH₃ D-glucitol 1218 CNF CH₃ SO₃H 1219 CN F CH₃ PO₃H₂ 1220 CN F CH₃ CHO 1221 CN F CH₃ COOH 1222CN F CH₃ CH₂OH 1223 CN F CH₃ sugar 1224 CN F CH₃ C-glycosyl compound1225 CN F Cl OH 1226 CN F Cl D-glucitol 1227 CN F Cl SO₃H 1228 CN F ClPO₃H₂ 1229 CN F Cl CHO 1230 CN F Cl COOH 1231 CN F Cl CH₂OH 1232 CN F Clsugar 1233 CN F Cl C-glycosyl compound 1234 CN F B(OH)₂ OH 1235 CN FB(OH)₂ D-glucitol 1236 CN F B(OH)₂ SO₃H 1237 CN F B(OH)₂ PO₃H₂ 1238 CN FB(OH)₂ CHO 1239 CN F B(OH)₂ COOH 1240 CN F B(OH)₂ CH₂OH 1241 CN F B(OH)₂sugar 1242 CN F B(OH)₂ C-glycosyl compound 1243 CN F SH OH 1244 CN F SHD-glucitol 1245 CN F SH SO₃H 1246 CN F SH PO₃H₂ 1247 CN F SH CHO 1248 CNF SH COOH 1249 CN F SH CH₂OH 1250 CN F SH sugar 1251 CN F SH C-glycosylcompound 1252 CN F OCH₃ OH 1253 CN F OCH₃ D-glucitol 1254 CN F OCH₃ SO₃H1255 CN F OCH₃ PO₃H₂ 1256 CN F OCH₃ CHO 1257 CN F OCH₃ COOH 1258 CN FOCH₃ CH₂OH 1259 CN F OCH₃ sugar 1260 CN F OCH₃ C-glycosyl compound 1261CN Cl H OH 1262 CN Cl H D-glucitol 1263 CN Cl H SO₃H 1264 CN Cl H PO₃H₂1265 CN Cl H CHO 1266 CN Cl H COOH 1267 CN Cl H CH₂OH 1268 CN Cl H sugar1269 CN Cl H C-glycosyl compound 1270 CN Cl OH OH 1271 CN Cl OHD-glucitol 1272 CN Cl OH SO₃H 1273 CN Cl OH PO₃H₂ 1274 CN Cl OH CHO 1275CN Cl OH COOH 1276 CN Cl OH CH₂OH 1277 CN Cl OH sugar 1278 CN Cl OHC-glycosyl compound 1279 CN Cl CH₃ OH 1280 CN Cl CH₃ D-glucitol 1281 CNCl CH₃ SO₃H 1282 CN Cl CH₃ PO₃H₂ 1283 CN Cl CH₃ CHO 1284 CN Cl CH₃ COOH1285 CN Cl CH₃ CH₂OH 1286 CN Cl CH₃ sugar 1287 CN Cl CH₃ C-glycosylcompound 1288 CN Cl Cl OH 1289 CN Cl Cl D-glucitol 1290 CN Cl Cl SO₃H1291 CN Cl Cl PO₃H₂ 1292 CN Cl Cl CHO 1293 CN Cl Cl COOH 1294 CN Cl ClCH₂OH 1295 CN Cl Cl sugar 1296 CN Cl Cl C-glycosyl compound 1297 CN ClB(OH)₂ OH 1298 CN Cl B(OH)₂ D-glucitol 1299 CN Cl B(OH)₂ SO₃H 1300 CN ClB(OH)₂ PO₃H₂ 1301 CN Cl B(OH)₂ CHO 1302 CN Cl B(OH)₂ COOH 1303 CN ClB(OH)₂ CH₂OH 1304 CN Cl B(OH)₂ sugar 1305 CN Cl B(OH)₂ C-glycosylcompound 1306 CN Cl SH OH 1307 CN Cl SH D-glucitol 1308 CN Cl SH SO₃H1309 CN Cl SH PO₃H₂ 1310 CN Cl SH CHO 1311 CN Cl SH COOH 1312 CN Cl SHCH₂OH 1313 CN Cl SH sugar 1314 CN Cl SH C-glycosyl compound 1315 CN ClOCH₃ OH 1316 CN Cl OCH₃ D-glucitol 1317 CN Cl OCH₃ SO₃H 1318 CN Cl OCH₃PO₃H₂ 1319 CN Cl OCH₃ CHO 1320 CN Cl OCH₃ COOH 1321 CN Cl OCH₃ CH₂OH1322 CN Cl OCH₃ sugar 1323 CN Cl OCH₃ C-glycosyl compound 1324 CN CN HOH 1325 CN CN H D-glucitol 1326 CN CN H SO₃H 1327 CN CN H PO₃H₂ 1328 CNCN H CHO 1329 CN CN H COOH 1330 CN CN H CH₂OH 1331 CN CN H sugar 1332 CNCN H C-glycosyl compound 1333 CN CN OH OH 1334 CN CN OH D-glucitol 1335CN CN OH SO₃H 1336 CN CN OH PO₃H₂ 1337 CN CN OH CHO 1338 CN CN OH COOH1339 CN CN OH CH₂OH 1340 CN CN OH sugar 1341 CN CN OH C-glycosylcompound 1342 CN CN CH₃ OH 1343 CN CN CH₃ D-glucitol 1344 CN CN CH₃ SO₃H1345 CN CN CH₃ PO₃H₂ 1346 CN CN CH₃ CHO 1347 CN CN CH₃ COOH 1348 CN CNCH₃ CH₂OH 1349 CN CN CH₃ sugar 1350 CN CN CH₃ C-glycosyl compound 1351CN CN Cl OH 1352 CN CN Cl D-glucitol 1353 CN CN Cl SO₃H 1354 CN CN ClPO₃H₂ 1355 CN CN Cl CHO 1356 CN CN Cl COOH 1357 CN CN Cl CH₂OH 1358 CNCN Cl sugar 1359 CN CN Cl C-glycosyl compound 1360 CN CN B(OH)₂ OH 1361CN CN B(OH)₂ D-glucitol 1362 CN CN B(OH)₂ SO₃H 1363 CN CN B(OH)₂ PO₃H₂1364 CN CN B(OH)₂ CHO 1365 CN CN B(OH)₂ COOH 1366 CN CN B(OH)₂ CH₂OH1367 CN CN B(OH)₂ sugar 1368 CN CN B(OH)₂ C-glycosyl compound 1369 CN CNSH OH 1370 CN CN SH D-glucitol 1371 CN CN SH SO₃H 1372 CN CN SH PO₃H₂1373 CN CN SH CHO 1374 CN CN SH COOH 1375 CN CN SH CH₂OH 1376 CN CN SHsugar 1377 CN CN SH C-glycosyl compound 1378 CN CN OCH₃ OH 1379 CN CNOCH₃ D-glucitol 1380 CN CN OCH₃ SO₃H 1381 CN CN OCH₃ PO₃H₂ 1382 CN CNOCH₃ CHO 1383 CN CN OCH₃ COOH 1384 CN CN OCH₃ CH₂OH 1385 CN CN OCH₃sugar 1386 CN CN OCH₃ C-glycosyl compound 1387 CN CH₃ ^(a) H OH 1388 CNCH₃ ^(a) H D-glucitol 1389 CN CH₃ ^(a) H SO₃H 1390 CN CH₃ ^(a) H PO₃H₂1391 CN CH₃ ^(a) H CHO 1392 CN CH₃ ^(a) H COOH 1393 CN CH₃ ^(a) H CH₂OH1394 CN CH₃ ^(a) H sugar 1395 CN CH₃ ^(a) H C-glycosyl compound 1396 CNCH₃ ^(a) OH OH 1397 CN CH₃ ^(a) OH D-glucitol 1398 CN CH₃ ^(a) OH SO₃H1399 CN CH₃ ^(a) OH PO₃H₂ 1400 CN CH₃ ^(a) OH CHO 1401 CN CH₃ ^(a) OHCOOH 1402 CN CH₃ ^(a) OH CH₂OH 1403 CN CH₃ ^(a) OH sugar 1404 CN CH₃^(a) OH C-glycosyl compound 1405 CN CH₃ ^(a) CH₃ OH 1406 CN CH₃ ^(a) CH₃D-glucitol 1407 CN CH₃ ^(a) CH₃ SO₃H 1408 CN CH₃ ^(a) CH₃ PO₃H₂ 1409 CNCH₃ ^(a) CH₃ CHO 1410 CN CH₃ ^(a) CH₃ COOH 1411 CN CH₃ ^(a) CH₃ CH₂OH1412 CN CH₃ ^(a) CH₃ sugar 1413 CN CH₃ ^(a) CH₃ C-glycosyl compound 1414CN CH₃ ^(a) Cl OH 1415 CN CH₃ ^(a) Cl D-glucitol 1416 CN CH₃ ^(a) ClSO₃H 1417 CN CH₃ ^(a) Cl PO₃H₂ 1418 CN CH₃ ^(a) Cl CHO 1419 CN CH₃ ^(a)Cl COOH 1420 CN CH₃ ^(a) Cl CH₂OH 1421 CN CH₃ ^(a) Cl sugar 1422 CN CH₃^(a) Cl C-glycosyl compound 1423 CN CH₃ ^(a) B(OH)₂ OH 1424 CN CH₃ ^(a)B(OH)₂ D-glucitol 1425 CN CH₃ ^(a) B(OH)₂ SO₃H 1426 CN CH₃ ^(a) B(OH)₂PO₃H₂ 1427 CN CH₃ ^(a) B(OH)₂ CHO 1428 CN CH₃ ^(a) B(OH)₂ COOH 1429 CNCH₃ ^(a) B(OH)₂ CH₂OH 1430 CN CH₃ ^(a) B(OH)₂ sugar 1431 CN CH₃ ^(a)B(OH)₂ C-glycosyl compound 1432 CN CH₃ ^(a) SH OH 1433 CN CH₃ ^(a) SHD-glucitol 1434 CN CH₃ ^(a) SH SO₃H 1435 CN CH₃ ^(a) SH PO₃H₂ 1436 CNCH₃ ^(a) SH CHO 1437 CN CH₃ ^(a) SH COOH 1438 CN CH₃ ^(a) SH CH₂OH 1439CN CH₃ ^(a) SH sugar 1440 CN CH₃ ^(a) SH C-glycosyl compound 1441 CN CH₃^(a) OCH₃ OH 1442 CN CH₃ ^(a) OCH₃ D-glucitol 1443 CN CH₃ ^(a) OCH₃ SO₃H1444 CN CH₃ ^(a) OCH₃ PO₃H₂ 1445 CN CH₃ ^(a) OCH₃ CHO 1446 CN CH₃ ^(a)OCH₃ COOH 1447 CN CH₃ ^(a) OCH₃ CH₂OH 1448 CN CH₃ ^(a) OCH₃ sugar 1449CN CH₃ ^(a) OCH₃ C-glycosyl compound 1450 CN OCH3^(b) H OH 1451 CNOCH3^(b) H D-glucitol 1452 CN OCH3^(b) H SO₃H 1453 CN OCH3^(b) H PO₃H₂1454 CN OCH3^(b) H CHO 1455 CN OCH3^(b) H COOH 1456 CN OCH3^(b) H CH₂OH1457 CN OCH3^(b) H sugar 1458 CN OCH3^(b) H C-glycosyl compound 1459 CNOCH3^(b) OH OH 1460 CN OCH3^(b) OH D-glucitol 1461 CN OCH3^(b) OH SO₃H1462 CN OCH3^(b) OH PO₃H₂ 1463 CN OCH3^(b) OH CHO 1464 CN OCH3^(b) OHCOOH 1465 CN OCH3^(b) OH CH₂OH 1466 CN OCH3^(b) OH sugar 1467 CNOCH3^(b) OH C-glycosyl compound 1468 CN OCH3^(b) CH₃ OH 1469 CN OCH3^(b)CH₃ D-glucitol 1470 CN OCH3^(b) CH₃ SO₃H 1471 CN OCH3^(b) CH₃ PO₃H₂ 1472CN OCH3^(b) CH₃ CHO 1473 CN OCH3^(b) CH₃ COOH 1474 CN OCH3^(b) CH₃ CH₂OH1475 CN OCH3^(b) CH₃ sugar 1476 CN OCH3^(b) CH₃ C-glycosyl compound 1477CN OCH3^(b) Cl OH 1478 CN OCH3^(b) Cl D-glucitol 1479 CN OCH3^(b) ClSO₃H 1480 CN OCH3^(b) Cl PO₃H₂ 1481 CN OCH3^(b) Cl CHO 1482 CN OCH3^(b)Cl COOH 1483 CN OCH3^(b) Cl CH₂OH 1484 CN OCH3^(b) Cl sugar 1485 CNOCH3^(b) Cl C-glycosyl compound 1486 CN OCH3^(b) B(OH)₂ OH 1487 CNOCH3^(b) B(OH)₂ D-glucitol 1488 CN OCH3^(b) B(OH)₂ SO₃H 1489 CN OCH3^(b)B(OH)₂ PO₃H₂ 1490 CN OCH3^(b) B(OH)₂ CHO 1491 CN OCH3^(b) B(OH)₂ COOH1492 CN OCH3^(b) B(OH)₂ CH₂OH 1493 CN OCH3^(b) B(OH)₂ sugar 1494 CNOCH3^(b) B(OH)₂ C-glycosyl compound 1495 CN OCH3^(b) SH OH 1496 CNOCH3^(b) SH D-glucitol 1497 CN OCH3^(b) SH SO₃H 1498 CN OCH3^(b) SHPO₃H₂ 1499 CN OCH3^(b) SH CHO 1500 CN OCH3^(b) SH COOH 1501 CN OCH3^(b)SH CH₂OH 1502 CN OCH3^(b) SH sugar 1503 CN OCH3^(b) SH C-glycosylcompound 1504 CN OCH3^(b) OCH₃ OH 1505 CN OCH3^(b) OCH₃ D-glucitol 1506CN OCH3^(b) OCH₃ SO₃H 1507 CN OCH3^(b) OCH₃ PO₃H₂ 1508 CN OCH3^(b) OCH₃CHO 1509 CN OCH3^(b) OCH₃ COOH 1510 CN OCH3^(b) OCH₃ CH₂OH 1511 CNOCH3^(b) OCH₃ sugar 1512 CN OCH3^(b) OCH₃ C-glycosyl compound 1513 CH₃^(a) H H OH 1514 CH₃ ^(a) H H D-glucitol 1515 CH₃ ^(a) H H SO₃H 1516 CH₃^(a) H H PO₃H₂ 1517 CH₃ ^(a) H H CHO 1518 CH₃ ^(a) H H COOH 1519 CH₃^(a) H H CH₂OH 1520 CH₃ ^(a) H H sugar 1521 CH₃ ^(a) H H C-glycosylcompound 1522 CH₃ ^(a) H OH OH 1523 CH₃ ^(a) H OH D-glucitol 1524 CH₃^(a) H OH SO₃H 1525 CH₃ ^(a) H OH PO₃H₂ 1526 CH₃ ^(a) H OH CHO 1527 CH₃^(a) H OH COOH 1528 CH₃ ^(a) H OH CH₂OH 1529 CH₃ ^(a) H OH sugar 1530CH₃ ^(a) H OH C-glycosyl compound 1531 CH₃ ^(a) H CH₃ OH 1532 CH₃ ^(a) HCH₃ D-glucitol 1533 CH₃ ^(a) H CH₃ SO₃H 1534 CH₃ ^(a) H CH₃ PO₃H₂ 1535CH₃ ^(a) H CH₃ CHO 1536 CH₃ ^(a) H CH₃ COOH 1537 CH₃ ^(a) H CH₃ CH₂OH1538 CH₃ ^(a) H CH₃ sugar 1539 CH₃ ^(a) H CH₃ C-glycosyl compound 1540CH₃ ^(a) H Cl OH 1541 CH₃ ^(a) H Cl D-glucitol 1542 CH₃ ^(a) H Cl SO₃H1543 CH₃ ^(a) H Cl PO₃H₂ 1544 CH₃ ^(a) H Cl CHO 1545 CH₃ ^(a) H Cl COOH1546 CH₃ ^(a) H Cl CH₂OH 1547 CH₃ ^(a) H Cl sugar 1548 CH₃ ^(a) H ClC-glycosyl compound 1549 CH₃ ^(a) H B(OH)₂ OH 1550 CH₃ ^(a) H B(OH)₂D-glucitol 1551 CH₃ ^(a) H B(OH)₂ SO₃H 1552 CH₃ ^(a) H B(OH)₂ PO₃H₂ 1553CH₃ ^(a) H B(OH)₂ CHO 1554 CH₃ ^(a) H B(OH)₂ COOH 1555 CH₃ ^(a) H B(OH)₂CH₂OH 1556 CH₃ ^(a) H B(OH)₂ sugar 1557 CH₃ ^(a) H B(OH)₂ C-glycosylcompound 1558 CH₃ ^(a) H SH OH 1559 CH₃ ^(a) H SH D-glucitol 1560 CH₃^(a) H SH SO₃H 1561 CH₃ ^(a) H SH PO₃H₂ 1562 CH₃ ^(a) H SH CHO 1563 CH₃^(a) H SH COOH 1564 CH₃ ^(a) H SH CH₂OH 1565 CH₃ ^(a) H SH sugar 1566CH₃ ^(a) H SH C-glycosyl compound 1567 CH₃ ^(a) H OCH₃ OH 1568 CH₃ ^(a)H OCH₃ D-glucitol 1569 CH₃ ^(a) H OCH₃ SO₃H 1570 CH₃ ^(a) H OCH₃ PO₃H₂1571 CH₃ ^(a) H OCH₃ CHO 1572 CH₃ ^(a) H OCH₃ COOH 1573 CH₃ ^(a) H OCH₃CH₂OH 1574 CH₃ ^(a) H OCH₃ sugar 1575 CH₃ ^(a) H OCH₃ C-glycosylcompound 1576 CH₃ ^(a) F H OH 1577 CH₃ ^(a) F H D-glucitol 1578 CH₃ ^(a)F H SO₃H 1579 CH₃ ^(a) F H PO₃H₂ 1580 CH₃ ^(a) F H CHO 1581 CH₃ ^(a) F HCOOH 1582 CH₃ ^(a) F H CH₂OH 1583 CH₃ ^(a) F H sugar 1584 CH₃ ^(a) F HC-glycosyl compound 1585 CH₃ ^(a) F OH OH 1586 CH₃ ^(a) F OH D-glucitol1587 CH₃ ^(a) F OH SO₃H 1588 CH₃ ^(a) F OH PO₃H₂ 1589 CH₃ ^(a) F OH CHO1590 CH₃ ^(a) F OH COOH 1591 CH₃ ^(a) F OH CH₂OH 1592 CH₃ ^(a) F OHsugar 1593 CH₃ ^(a) F OH C-glycosyl compound 1594 CH₃ ^(a) F CH₃ OH 1595CH₃ ^(a) F CH₃ D-glucitol 1596 CH₃ ^(a) F CH₃ SO₃H 1597 CH₃ ^(a) F CH₃PO₃H₂ 1598 CH₃ ^(a) F CH₃ CHO 1599 CH₃ ^(a) F CH₃ COOH 1600 CH₃ ^(a) FCH₃ CH₂OH 1601 CH₃ ^(a) F CH₃ sugar 1602 CH₃ ^(a) F CH₃ C-glycosylcompound 1603 CH₃ ^(a) F Cl OH 1604 CH₃ ^(a) F Cl D-glucitol 1605 CH₃^(a) F Cl SO₃H 1606 CH₃ ^(a) F Cl PO₃H₂ 1607 CH₃ ^(a) F Cl CHO 1608 CH₃^(a) F Cl COOH 1609 CH₃ ^(a) F Cl CH₂OH 1610 CH₃ ^(a) F Cl sugar 1611CH₃ ^(a) F Cl C-glycosyl compound 1612 CH₃ ^(a) F B(OH)₂ OH 1613 CH₃^(a) F B(OH)₂ D-glucitol 1614 CH₃ ^(a) F B(OH)₂ SO₃H 1615 CH₃ ^(a) FB(OH)₂ PO₃H₂ 1616 CH₃ ^(a) F B(OH)₂ CHO 1617 CH₃ ^(a) F B(OH)₂ COOH 1618CH₃ ^(a) F B(OH)₂ CH₂OH 1619 CH₃ ^(a) F B(OH)₂ sugar 1620 CH₃ ^(a) FB(OH)₂ C-glycosyl compound 1621 CH₃ ^(a) F SH OH 1622 CH₃ ^(a) F SHD-glucitol 1623 CH₃ ^(a) F SH SO₃H 1624 CH₃ ^(a) F SH PO₃H₂ 1625 CH₃^(a) F SH CHO 1626 CH₃ ^(a) F SH COOH 1627 CH₃ ^(a) F SH CH₂OH 1628 CH₃^(a) F SH sugar 1629 CH₃ ^(a) F SH C-glycosyl compound 1630 CH₃ ^(a) FOCH₃ OH 1631 CH₃ ^(a) F OCH₃ D-glucitol 1632 CH₃ ^(a) F OCH₃ SO₃H 1633CH₃ ^(a) F OCH₃ PO₃H₂ 1634 CH₃ ^(a) F OCH₃ CHO 1635 CH₃ ^(a) F OCH₃ COOH1636 CH₃ ^(a) F OCH₃ CH₂OH 1637 CH₃ ^(a) F OCH₃ sugar 1638 CH₃ ^(a) FOCH₃ C-glycosyl compound 1639 CH₃ ^(a) Cl H OH 1640 CH₃ ^(a) Cl HD-glucitol 1641 CH₃ ^(a) Cl H SO₃H 1642 CH₃ ^(a) Cl H PO₃H₂ 1643 CH₃^(a) Cl H CHO 1644 CH₃ ^(a) Cl H COOH 1645 CH₃ ^(a) Cl H CH₂OH 1646 CH₃^(a) Cl H sugar 1647 CH₃ ^(a) Cl H C-glycosyl compound 1648 CH₃ ^(a) ClOH OH 1649 CH₃ ^(a) Cl OH D-glucitol 1650 CH₃ ^(a) Cl OH SO₃H 1651 CH₃^(a) Cl OH PO₃H₂ 1652 CH₃ ^(a) Cl OH CHO 1653 CH₃ ^(a) Cl OH COOH 1654CH₃ ^(a) Cl OH CH₂OH 1655 CH₃ ^(a) Cl OH sugar 1656 CH₃ ^(a) Cl OHC-glycosyl compound 1657 CH₃ ^(a) Cl CH₃ OH 1658 CH₃ ^(a) Cl CH₃D-glucitol 1659 CH₃ ^(a) Cl CH₃ SO₃H 1660 CH₃ ^(a) Cl CH₃ PO₃H₂ 1661 CH₃^(a) Cl CH₃ CHO 1662 CH₃ ^(a) Cl CH₃ COOH 1663 CH₃ ^(a) Cl CH₃ CH₂OH1664 CH₃ ^(a) Cl CH₃ sugar 1665 CH₃ ^(a) Cl CH₃ C-glycosyl compound 1666CH₃ ^(a) Cl Cl OH 1667 CH₃ ^(a) Cl Cl D-glucitol 1668 CH₃ ^(a) Cl ClSO₃H 1669 CH₃ ^(a) Cl Cl PO₃H₂ 1670 CH₃ ^(a) Cl Cl CHO 1671 CH₃ ^(a) ClCl COOH 1672 CH₃ ^(a) Cl Cl CH₂OH 1673 CH₃ ^(a) Cl Cl sugar 1674 CH₃^(a) Cl Cl C-glycosyl compound 1675 CH₃ ^(a) Cl B(OH)₂ OH 1676 CH₃ ^(a)Cl B(OH)₂ D-glucitol 1677 CH₃ ^(a) Cl B(OH)₂ SO₃H 1678 CH₃ ^(a) ClB(OH)₂ PO₃H₂ 1679 CH₃ ^(a) Cl B(OH)₂ CHO 1680 CH₃ ^(a) Cl B(OH)₂ COOH1681 CH₃ ^(a) Cl B(OH)₂ CH₂OH 1682 CH₃ ^(a) Cl B(OH)₂ sugar 1683 CH₃^(a) Cl B(OH)₂ C-glycosyl compound 1684 CH₃ ^(a) Cl SH OH 1685 CH₃ ^(a)Cl SH D-glucitol 1686 CH₃ ^(a) Cl SH SO₃H 1687 CH₃ ^(a) Cl SH PO₃H₂ 1688CH₃ ^(a) Cl SH CHO 1689 CH₃ ^(a) Cl SH COOH 1690 CH₃ ^(a) Cl SH CH₂OH1691 CH₃ ^(a) Cl SH sugar 1692 CH₃ ^(a) Cl SH C-glycosyl compound 1693CH₃ ^(a) Cl OCH₃ OH 1694 CH₃ ^(a) Cl OCH₃ D-glucitol 1695 CH₃ ^(a) ClOCH₃ SO₃H 1696 CH₃ ^(a) Cl OCH₃ PO₃H₂ 1697 CH₃ ^(a) Cl OCH₃ CHO 1698 CH₃^(a) Cl OCH₃ COOH 1699 CH₃ ^(a) Cl OCH₃ CH₂OH 1700 CH₃ ^(a) Cl OCH₃sugar 1701 CH₃ ^(a) Cl OCH₃ C-glycosyl compound 1702 CH₃ ^(a) CN H OH1703 CH₃ ^(a) CN H D-glucitol 1704 CH₃ ^(a) CN H SO₃H 1705 CH₃ ^(a) CN HPO₃H₂ 1706 CH₃ ^(a) CN H CHO 1707 CH₃ ^(a) CN H COOH 1708 CH₃ ^(a) CN HCH₂OH 1709 CH₃ ^(a) CN H sugar 1710 CH₃ ^(a) CN H C-glycosyl compound1711 CH₃ ^(a) CN OH OH 1712 CH₃ ^(a) CN OH D-glucitol 1713 CH₃ ^(a) CNOH SO₃H 1714 CH₃ ^(a) CN OH PO₃H₂ 1715 CH₃ ^(a) CN OH CHO 1716 CH₃ ^(a)CN OH COOH 1717 CH₃ ^(a) CN OH CH₂OH 1718 CH₃ ^(a) CN OH sugar 1719 CH₃^(a) CN OH C-glycosyl compound 1720 CH₃ ^(a) CN CH₃ OH 1721 CH₃ ^(a) CNCH₃ D-glucitol 1722 CH₃ ^(a) CN CH₃ SO₃H 1723 CH₃ ^(a) CN CH₃ PO₃H₂ 1724CH₃ ^(a) CN CH₃ CHO 1725 CH₃ ^(a) CN CH₃ COOH 1726 CH₃ ^(a) CN CH₃ CH₂OH1727 CH₃ ^(a) CN CH₃ sugar 1728 CH₃ ^(a) CN CH₃ C-glycosyl compound 1729CH₃ ^(a) CN Cl OH 1730 CH₃ ^(a) CN Cl D-glucitol 1731 CH₃ ^(a) CN ClSO₃H 1732 CH₃ ^(a) CN Cl PO₃H₂ 1733 CH₃ ^(a) CN Cl CHO 1734 CH₃ ^(a) CNCl COOH 1735 CH₃ ^(a) CN Cl CH₂OH 1736 CH₃ ^(a) CN Cl sugar 1737 CH₃^(a) CN Cl C-glycosyl compound 1738 CH₃ ^(a) CN B(OH)₂ OH 1739 CH₃ ^(a)CN B(OH)₂ D-glucitol 1740 CH₃ ^(a) CN B(OH)₂ SO₃H 1741 CH₃ ^(a) CNB(OH)₂ PO₃H₂ 1742 CH₃ ^(a) CN B(OH)₂ CHO 1743 CH₃ ^(a) CN B(OH)₂ COOH1744 CH₃ ^(a) CN B(OH)₂ CH₂OH 1745 CH₃ ^(a) CN B(OH)₂ sugar 1746 CH₃^(a) CN B(OH)₂ C-glycosyl compound 1747 CH₃ ^(a) CN SH OH 1748 CH₃ ^(a)CN SH D-glucitol 1749 CH₃ ^(a) CN SH SO₃H 1750 CH₃ ^(a) CN SH PO₃H₂ 1751CH₃ ^(a) CN SH CHO 1752 CH₃ ^(a) CN SH COOH 1753 CH₃ ^(a) CN SH CH₂OH1754 CH₃ ^(a) CN SH sugar 1755 CH₃ ^(a) CN SH C-glycosyl compound 1756CH₃ ^(a) CN OCH₃ OH 1757 CH₃ ^(a) CN OCH₃ D-glucitol 1758 CH₃ ^(a) CNOCH₃ SO₃H 1759 CH₃ ^(a) CN OCH₃ PO₃H₂ 1760 CH₃ ^(a) CN OCH₃ CHO 1761 CH₃^(a) CN OCH₃ COOH 1762 CH₃ ^(a) CN OCH₃ CH₂OH 1763 CH₃ ^(a) CN OCH₃sugar 1764 CH₃ ^(a) CN OCH₃ C-glycosyl compound 1765 CH₃ ^(a) CH₃ ^(a) HOH 1766 CH₃ ^(a) CH₃ ^(a) H D-glucitol 1767 CH₃ ^(a) CH₃ ^(a) H SO₃H1768 CH₃ ^(a) CH₃ ^(a) H PO₃H₂ 1769 CH₃ ^(a) CH₃ ^(a) H CHO 1770 CH₃^(a) CH₃ ^(a) H COOH 1771 CH₃ ^(a) CH₃ ^(a) H CH₂OH 1772 CH₃ ^(a) CH₃^(a) H sugar 1773 CH₃ ^(a) CH₃ ^(a) H C-glycosyl compound 1774 CH₃ ^(a)CH₃ ^(a) OH OH 1775 CH₃ ^(a) CH₃ ^(a) OH D-glucitol 1776 CH₃ ^(a) CH₃^(a) OH SO₃H 1777 CH₃ ^(a) CH₃ ^(a) OH PO₃H₂ 1778 CH₃ ^(a) CH₃ ^(a) OHCHO 1779 CH₃ ^(a) CH₃ ^(a) OH COOH 1780 CH₃ ^(a) CH₃ ^(a) OH CH₂OH 1781CH₃ ^(a) CH₃ ^(a) OH sugar 1782 CH₃ ^(a) CH₃ ^(a) OH C-glycosyl compound1783 CH₃ ^(a) CH₃ ^(a) CH₃ OH 1784 CH₃ ^(a) CH₃ ^(a) CH₃ D-glucitol 1785CH₃ ^(a) CH₃ ^(a) CH₃ SO₃H 1786 CH₃ ^(a) CH₃ ^(a) CH₃ PO₃H₂ 1787 CH₃^(a) CH₃ ^(a) CH₃ CHO 1788 CH₃ ^(a) CH₃ ^(a) CH₃ COOH 1789 CH₃ ^(a) CH₃^(a) CH₃ CH₂OH 1790 CH₃ ^(a) CH₃ ^(a) CH₃ sugar 1791 CH₃ ^(a) CH₃ ^(a)CH₃ C-glycosyl compound 1792 CH₃ ^(a) CH₃ ^(a) Cl OH 1793 CH₃ ^(a) CH₃^(a) Cl D-glucitol 1794 CH₃ ^(a) CH₃ ^(a) Cl SO₃H 1795 CH₃ ^(a) CH₃ ^(a)Cl PO₃H₂ 1796 CH₃ ^(a) CH₃ ^(a) Cl CHO 1797 CH₃ ^(a) CH₃ ^(a) Cl COOH1798 CH₃ ^(a) CH₃ ^(a) Cl CH₂OH 1799 CH₃ ^(a) CH₃ ^(a) Cl sugar 1800 CH₃^(a) CH₃ ^(a) Cl C-glycosyl compound 1801 CH₃ ^(a) CH₃ ^(a) B(OH)₂ OH1802 CH₃ ^(a) CH₃ ^(a) B(OH)₂ D-glucitol 1803 CH₃ ^(a) CH₃ ^(a) B(OH)₂SO₃H 1804 CH₃ ^(a) CH₃ ^(a) B(OH)₂ PO₃H₂ 1805 CH₃ ^(a) CH₃ ^(a) B(OH)₂CHO 1806 CH₃ ^(a) CH₃ ^(a) B(OH)₂ COOH 1807 CH₃ ^(a) CH₃ ^(a) B(OH)₂CH₂OH 1808 CH₃ ^(a) CH₃ ^(a) B(OH)₂ sugar 1809 CH₃ ^(a) CH₃ ^(a) B(OH)₂C-glycosyl compound 1810 CH₃ ^(a) CH₃ ^(a) SH OH 1811 CH₃ ^(a) CH₃ ^(a)SH D-glucitol 1812 CH₃ ^(a) CH₃ ^(a) SH SO₃H 1813 CH₃ ^(a) CH₃ ^(a) SHPO₃H₂ 1814 CH₃ ^(a) CH₃ ^(a) SH CHO 1815 CH₃ ^(a) CH₃ ^(a) SH COOH 1816CH₃ ^(a) CH₃ ^(a) SH CH₂OH 1817 CH₃ ^(a) CH₃ ^(a) SH sugar 1818 CH₃ ^(a)CH₃ ^(a) SH C-glycosyl compound 1819 CH₃ ^(a) CH₃ ^(a) OCH₃ OH 1820 CH₃^(a) CH₃ ^(a) OCH₃ D-glucitol 1821 CH₃ ^(a) CH₃ ^(a) OCH₃ SO₃H 1822 CH₃^(a) CH₃ ^(a) OCH₃ PO₃H₂ 1823 CH₃ ^(a) CH₃ ^(a) OCH₃ CHO 1824 CH₃ ^(a)CH₃ ^(a) OCH₃ COOH 1825 CH₃ ^(a) CH₃ ^(a) OCH₃ CH₂OH 1826 CH₃ ^(a) CH₃^(a) OCH₃ sugar 1827 CH₃ ^(a) CH₃ ^(a) OCH₃ C-glycosyl compound 1828 CH₃^(a) OCH3^(b) H OH 1829 CH₃ ^(a) OCH3^(b) H D-glucitol 1830 CH₃ ^(a)OCH3^(b) H SO₃H 1831 CH₃ ^(a) OCH3^(b) H PO₃H₂ 1832 CH₃ ^(a) OCH3^(b) HCHO 1833 CH₃ ^(a) OCH3^(b) H COOH 1834 CH₃ ^(a) OCH3^(b) H CH₂OH 1835CH₃ ^(a) OCH3^(b) H sugar 1836 CH₃ ^(a) OCH3^(b) H C-glycosyl compound1837 CH₃ ^(a) OCH3^(b) OH OH 1838 CH₃ ^(a) OCH3^(b) OH D-glucitol 1839CH₃ ^(a) OCH3^(b) OH SO₃H 1840 CH₃ ^(a) OCH3^(b) OH PO₃H₂ 1841 CH₃ ^(a)OCH3^(b) OH CHO 1842 CH₃ ^(a) OCH3^(b) OH COOH 1843 CH₃ ^(a) OCH3^(b) OHCH₂OH 1844 CH₃ ^(a) OCH3^(b) OH sugar 1845 CH₃ ^(a) OCH3^(b) OHC-glycosyl compound 1846 CH₃ ^(a) OCH3^(b) CH₃ OH 1847 CH₃ ^(a) OCH3^(b)CH₃ D-glucitol 1848 CH₃ ^(a) OCH3^(b) CH₃ SO₃H 1849 CH₃ ^(a) OCH3^(b)CH₃ PO₃H₂ 1850 CH₃ ^(a) OCH3^(b) CH₃ CHO 1851 CH₃ ^(a) OCH3^(b) CH₃ COOH1852 CH₃ ^(a) OCH3^(b) CH₃ CH₂OH 1853 CH₃ ^(a) OCH3^(b) CH₃ sugar 1854CH₃ ^(a) OCH3^(b) CH₃ C-glycosyl compound 1855 CH₃ ^(a) OCH3^(b) Cl OH1856 CH₃ ^(a) OCH3^(b) Cl D-glucitol 1857 CH₃ ^(a) OCH3^(b) Cl SO₃H 1858CH₃ ^(a) OCH3^(b) Cl PO₃H₂ 1859 CH₃ ^(a) OCH3^(b) Cl CHO 1860 CH₃ ^(a)OCH3^(b) Cl COOH 1861 CH₃ ^(a) OCH3^(b) Cl CH₂OH 1862 CH₃ ^(a) OCH3^(b)Cl sugar 1863 CH₃ ^(a) OCH3^(b) Cl C-glycosyl compound 1864 CH₃ ^(a)OCH3^(b) B(OH)₂ OH 1865 CH₃ ^(a) OCH3^(b) B(OH)₂ D-glucitol 1866 CH₃^(a) OCH3^(b) B(OH)₂ SO₃H 1867 CH₃ ^(a) OCH3^(b) B(OH)₂ PO₃H₂ 1868 CH₃^(a) OCH3^(b) B(OH)₂ CHO 1869 CH₃ ^(a) OCH3^(b) B(OH)₂ COOH 1870 CH₃^(a) OCH3^(b) B(OH)₂ CH₂OH 1871 CH₃ ^(a) OCH3^(b) B(OH)₂ sugar 1872 CH₃^(a) OCH3^(b) B(OH)₂ C-glycosyl compound 1873 CH₃ ^(a) OCH3^(b) SH OH1874 CH₃ ^(a) OCH3^(b) SH D-glucitol 1875 CH₃ ^(a) OCH3^(b) SH SO₃H 1876CH₃ ^(a) OCH3^(b) SH PO₃H₂ 1877 CH₃ ^(a) OCH3^(b) SH CHO 1878 CH₃ ^(a)OCH3^(b) SH COOH 1879 CH₃ ^(a) OCH3^(b) SH CH₂OH 1880 CH₃ ^(a) OCH3^(b)SH sugar 1881 CH₃ ^(a) OCH3^(b) SH C-glycosyl compound 1882 CH₃ ^(a)OCH3^(b) OCH₃ OH 1883 CH₃ ^(a) OCH3^(b) OCH₃ D-glucitol 1884 CH₃ ^(a)OCH3^(b) OCH₃ SO₃H 1885 CH₃ ^(a) OCH3^(b) OCH₃ PO₃H₂ 1886 CH₃ ^(a)OCH3^(b) OCH₃ CHO 1887 CH₃ ^(a) OCH3^(b) OCH₃ COOH 1888 CH₃ ^(a)OCH3^(b) OCH₃ CH₂OH 1889 CH₃ ^(a) OCH3^(b) OCH₃ sugar 1890 CH₃ ^(a)OCH3^(b) OCH₃ C-glycosyl compound 1891 OCH3^(b) H H OH 1892 OCH3^(b) H HD-glucitol 1893 OCH3^(b) H H SO₃H 1894 OCH3^(b) H H PO₃H₂ 1895 OCH3^(b)H H CHO 1896 OCH3^(b) H H COOH 1897 OCH3^(b) H H CH₂OH 1898 OCH3^(b) H Hsugar 1899 OCH3^(b) H H C-glycosyl compound 1900 OCH3^(b) H OH OH 1901OCH3^(b) H OH D-glucitol 1902 OCH3^(b) H OH SO₃H 1903 OCH3^(b) H OHPO₃H₂ 1904 OCH3^(b) H OH CHO 1905 OCH3^(b) H OH COOH 1906 OCH3^(b) H OHCH₂OH 1907 OCH3^(b) H OH sugar 1908 OCH3^(b) H OH C-glycosyl compound1909 OCH3^(b) H CH3 OH 1910 OCH3^(b) H CH3 D-glucitol 1911 OCH3^(b) HCH3 SO₃H 1912 OCH3^(b) H CH3 PO₃H₂ 1913 OCH3^(b) H CH3 CHO 1914 OCH3^(b)H CH3 COOH 1915 OCH3^(b) H CH3 CH₂OH 1916 OCH3^(b) H CH3 sugar 1917OCH3^(b) H CH3 C-glycosyl compound 1918 OCH3^(b) H Cl OH 1919 OCH3^(b) HCl D-glucitol 1920 OCH3^(b) H Cl SO₃H 1921 OCH3^(b) H Cl PO₃H₂ 1922OCH3^(b) H Cl CHO 1923 OCH3^(b) H Cl COOH 1924 OCH3^(b) H Cl CH₂OH 1925OCH3^(b) H Cl sugar 1926 OCH3^(b) H Cl C-glycosyl compound 1927 OCH3^(b)H B(OH)₂ OH 1928 OCH3^(b) H B(OH)₂ D-glucitol 1929 OCH3^(b) H B(OH)₂SO₃H 1930 OCH3^(b) H B(OH)₂ PO₃H₂ 1931 OCH3^(b) H B(OH)₂ CHO 1932OCH3^(b) H B(OH)₂ COOH 1933 OCH3^(b) H B(OH)₂ CH₂OH 1934 OCH3^(b) HB(OH)₂ sugar 1935 OCH3^(b) H B(OH)₂ C-glycosyl compound 1936 OCH3^(b) HSH OH 1937 OCH3^(b) H SH D-glucitol 1938 OCH3^(b) H SH SO₃H 1939OCH3^(b) H SH PO₃H₂ 1940 OCH3^(b) H SH CHO 1941 OCH3^(b) H SH COOH 1942OCH3^(b) H SH CH₂OH 1943 OCH3^(b) H SH sugar 1944 OCH3^(b) H SHC-glycosyl compound 1945 OCH3^(b) H OCH3 OH 1946 OCH3^(b) H OCH3D-glucitol 1947 OCH3^(b) H OCH3 SO₃H 1948 OCH3^(b) H OCH3 PO₃H₂ 1949OCH3^(b) H OCH3 CHO 1950 OCH3^(b) H OCH3 COOH 1951 OCH3^(b) H OCH3 CH₂OH1952 OCH3^(b) H OCH3 sugar 1953 OCH3^(b) H OCH3 C-glycosyl compound 1954OCH3^(b) F H OH 1955 OCH3^(b) F H D-glucitol 1956 OCH3^(b) F H SO₃H 1957OCH3^(b) F H PO₃H₂ 1958 OCH3^(b) F H CHO 1959 OCH3^(b) F H COOH 1960OCH3^(b) F H CH₂OH 1961 OCH3^(b) F H sugar 1962 OCH3^(b) F H C-glycosylcompound 1963 OCH3^(b) F OH OH 1964 OCH3^(b) F OH D-glucitol 1965OCH3^(b) F OH SO₃H 1966 OCH3^(b) F OH PO₃H₂ 1967 OCH3^(b) F OH CHO 1968OCH3^(b) F OH COOH 1969 OCH3^(b) F OH CH₂OH 1970 OCH3^(b) F OH sugar1971 OCH3^(b) F OH C-glycosyl compound 1972 OCH3^(b) F CH3 OH 1973OCH3^(b) F CH3 D-glucitol 1974 OCH3^(b) F CH3 SO₃H 1975 OCH3^(b) F CH3PO₃H₂ 1976 OCH3^(b) F CH3 CHO 1977 OCH3^(b) F CH3 COOH 1978 OCH3^(b) FCH3 CH₂OH 1979 OCH3^(b) F CH3 sugar 1980 OCH3^(b) F CH3 C-glycosylcompound 1981 OCH3^(b) F Cl OH 1982 OCH3^(b) F Cl D-glucitol 1983OCH3^(b) F Cl SO₃H 1984 OCH3^(b) F Cl PO₃H₂ 1985 OCH3^(b) F Cl CHO 1986OCH3^(b) F Cl COOH 1987 OCH3^(b) F Cl CH₂OH 1988 OCH3^(b) F Cl sugar1989 OCH3^(b) F Cl C-glycosyl compound 1990 OCH3^(b) F B(OH)₂ OH 1991OCH3^(b) F B(OH)₂ D-glucitol 1992 OCH3^(b) F B(OH)₂ SO₃H 1993 OCH3^(b) FB(OH)₂ PO₃H₂ 1994 OCH3^(b) F B(OH)₂ CHO 1995 OCH3^(b) F B(OH)₂ COOH 1996OCH3^(b) F B(OH)₂ CH₂OH 1997 OCH3^(b) F B(OH)₂ sugar 1998 OCH3^(b) FB(OH)₂ C-glycosyl compound 1999 OCH3^(b) F SH OH 2000 OCH3^(b) F SHD-glucitol 2001 OCH3^(b) F SH SO₃H 2002 OCH3^(b) F SH PO₃H₂ 2003OCH3^(b) F SH CHO 2004 OCH3^(b) F SH COOH 2005 OCH3^(b) F SH CH₂OH 2006OCH3^(b) F SH sugar 2007 OCH3^(b) F SH C-glycosyl compound 2008 OCH3^(b)F OCH3 OH 2009 OCH3^(b) F OCH3 D-glucitol 2010 OCH3^(b) F OCH3 SO₃H 2011OCH3^(b) F OCH3 PO₃H₂ 2012 OCH3^(b) F OCH3 CHO 2013 OCH3^(b) F OCH3 COOH2014 OCH3^(b) F OCH3 CH₂OH 2015 OCH3^(b) F OCH3 sugar 2016 OCH3^(b) FOCH3 C-glycosyl compound 2017 OCH3^(b) Cl H OH 2018 OCH3^(b) Cl HD-glucitol 2019 OCH3^(b) Cl H SO₃H 2020 OCH3^(b) Cl H PO₃H₂ 2021OCH3^(b) Cl H CHO 2022 OCH3^(b) Cl H COOH 2023 OCH3^(b) Cl H CH₂OH 2024OCH3^(b) Cl H sugar 2025 OCH3^(b) Cl H C-glycosyl compound 2026 OCH3^(b)Cl OH OH 2027 OCH3^(b) Cl OH D-glucitol 2028 OCH3^(b) Cl OH SO₃H 2029OCH3^(b) Cl OH PO₃H₂ 2030 OCH3^(b) Cl OH CHO 2031 OCH3^(b) Cl OH COOH2032 OCH3^(b) Cl OH CH₂OH 2033 OCH3^(b) Cl OH sugar 2034 OCH3^(b) Cl OHC-glycosyl compound 2035 OCH3^(b) Cl CH3 OH 2036 OCH3^(b) Cl CH3D-glucitol 2037 OCH3^(b) Cl CH3 SO₃H 2038 OCH3^(b) Cl CH3 PO₃H₂ 2039OCH3^(b) Cl CH3 CHO 2040 OCH3^(b) Cl CH3 COOH 2041 OCH3^(b) Cl CH3 CH₂OH2042 OCH3^(b) Cl CH3 sugar 2043 OCH3^(b) Cl CH3 C-glycosyl compound 2044OCH3^(b) Cl Cl OH 2045 OCH3^(b) Cl Cl D-glucitol 2046 OCH3^(b) Cl ClSO₃H 2047 OCH3^(b) Cl Cl PO₃H₂ 2048 OCH3^(b) Cl Cl CHO 2049 OCH3^(b) ClCl COOH 2050 OCH3^(b) Cl Cl CH₂OH 2051 OCH3^(b) Cl Cl sugar 2052OCH3^(b) Cl Cl C-glycosyl compound 2053 OCH3^(b) Cl B(OH)₂ OH 2054OCH3^(b) Cl B(OH)₂ D-glucitol 2055 OCH3^(b) Cl B(OH)₂ SO₃H 2056 OCH3^(b)Cl B(OH)₂ PO₃H₂ 2057 OCH3^(b) Cl B(OH)₂ CHO 2058 OCH3^(b) Cl B(OH)₂ COOH2059 OCH3^(b) Cl B(OH)₂ CH₂OH 2060 OCH3^(b) Cl B(OH)₂ sugar 2061OCH3^(b) Cl B(OH)₂ C-glycosyl compound 2062 OCH3^(b) Cl SH OH 2063OCH3^(b) Cl SH D-glucitol 2064 OCH3^(b) Cl SH SO₃H 2065 OCH3^(b) Cl SHPO₃H₂ 2066 OCH3^(b) Cl SH CHO 2067 OCH3^(b) Cl SH COOH 2068 OCH3^(b) ClSH CH₂OH 2069 OCH3^(b) Cl SH sugar 2070 OCH3^(b) Cl SH C-glycosylcompound 2071 OCH3^(b) Cl OCH3 OH 2072 OCH3^(b) Cl OCH3 D-glucitol 2073OCH3^(b) Cl OCH3 SO₃H 2074 OCH3^(b) Cl OCH3 PO₃H₂ 2075 OCH3^(b) Cl OCH3CHO 2076 OCH3^(b) Cl OCH3 COOH 2077 OCH3^(b) Cl OCH3 CH₂OH 2078 OCH3^(b)Cl OCH3 sugar 2079 OCH3^(b) Cl OCH3 C-glycosyl compound 2080 OCH3^(b) CNH OH 2081 OCH3^(b) CN H D-glucitol 2082 OCH3^(b) CN H SO₃H 2083 OCH3^(b)CN H PO₃H₂ 2084 OCH3^(b) CN H CHO 2085 OCH3^(b) CN H COOH 2086 OCH3^(b)CN H CH₂OH 2087 OCH3^(b) CN H sugar 2088 OCH3^(b) CN H C-glycosylcompound 2089 OCH3^(b) CN OH OH 2090 OCH3^(b) CN OH D-glucitol 2091OCH3^(b) CN OH SO₃H 2092 OCH3^(b) CN OH PO₃H₂ 2093 OCH3^(b) CN OH CHO2094 OCH3^(b) CN OH COOH 2095 OCH3^(b) CN OH CH₂OH 2096 OCH3^(b) CN OHsugar 2097 OCH3^(b) CN OH C-glycosyl compound 2098 OCH3^(b) CN CH3 OH2099 OCH3^(b) CN CH3 D-glucitol 2100 OCH3^(b) CN CH3 SO₃H 2101 OCH3^(b)CN CH3 PO₃H₂ 2102 OCH3^(b) CN CH3 CHO 2103 OCH3^(b) CN CH3 COOH 2104OCH3^(b) CN CH3 CH₂OH 2105 OCH3^(b) CN CH3 sugar 2106 OCH3^(b) CN CH3C-glycosyl compound 2107 OCH3^(b) CN Cl OH 2108 OCH3^(b) CN ClD-glucitol 2109 OCH3^(b) CN Cl SO₃H 2110 OCH3^(b) CN Cl PO₃H₂ 2111OCH3^(b) CN Cl CHO 2112 OCH3^(b) CN Cl COOH 2113 OCH3^(b) CN Cl CH₂OH2114 OCH3^(b) CN Cl sugar 2115 OCH3^(b) CN Cl C-glycosyl compound 2116OCH3^(b) CN B(OH)₂ OH 2117 OCH3^(b) CN B(OH)₂ D-glucitol 2118 OCH3^(b)CN B(OH)₂ SO₃H 2119 OCH3^(b) CN B(OH)₂ PO₃H₂ 2120 OCH3^(b) CN B(OH)₂ CHO2121 OCH3^(b) CN B(OH)₂ COOH 2122 OCH3^(b) CN B(OH)₂ CH₂OH 2123 OCH3^(b)CN B(OH)₂ sugar 2124 OCH3^(b) CN B(OH)₂ C-glycosyl compound 2125OCH3^(b) CN SH OH 2126 OCH3^(b) CN SH D-glucitol 2127 OCH3^(b) CN SHSO₃H 2128 OCH3^(b) CN SH PO₃H₂ 2129 OCH3^(b) CN SH CHO 2130 OCH3^(b) CNSH COOH 2131 OCH3^(b) CN SH CH₂OH 2132 OCH3^(b) CN SH sugar 2133OCH3^(b) CN SH C-glycosyl compound 2134 OCH3^(b) CN OCH3 OH 2135OCH3^(b) CN OCH3 D-glucitol 2136 OCH3^(b) CN OCH3 SO₃H 2137 OCH3^(b) CNOCH3 PO₃H₂ 2138 OCH3^(b) CN OCH3 CHO 2139 OCH3^(b) CN OCH3 COOH 2140OCH3^(b) CN OCH3 CH₂OH 2141 OCH3^(b) CN OCH3 sugar 2142 OCH3^(b) CN OCH3C-glycosyl compound 2143 OCH3^(b) CH₃ ^(a) H OH 2144 OCH3^(b) CH₃ ^(a) HD-glucitol 2145 OCH3^(b) CH₃ ^(a) H SO₃H 2146 OCH3^(b) CH₃ ^(a) H PO₃H₂2147 OCH3^(b) CH₃ ^(a) H CHO 2148 OCH3^(b) CH₃ ^(a) H COOH 2149 OCH3^(b)CH₃ ^(a) H CH₂OH 2150 OCH3^(b) CH₃ ^(a) H sugar 2151 OCH3^(b) CH₃ ^(a) HC-glycosyl compound 2152 OCH3^(b) CH₃ ^(a) OH OH 2153 OCH3^(b) CH₃ ^(a)OH D-glucitol 2154 OCH3^(b) CH₃ ^(a) OH SO₃H 2155 OCH3^(b) CH₃ ^(a) OHPO₃H₂ 2156 OCH3^(b) CH₃ ^(a) OH CHO 2157 OCH3^(b) CH₃ ^(a) OH COOH 2158OCH3^(b) CH₃ ^(a) OH CH₂OH 2159 OCH3^(b) CH₃ ^(a) OH sugar 2160 OCH3^(b)CH₃ ^(a) OH C-glycosyl compound 2161 OCH3^(b) CH₃ ^(a) CH3 OH 2162OCH3^(b) CH₃ ^(a) CH3 D-glucitol 2163 OCH3^(b) CH₃ ^(a) CH3 SO₃H 2164OCH3^(b) CH₃ ^(a) CH3 PO₃H₂ 2165 OCH3^(b) CH₃ ^(a) CH3 CHO 2166 OCH3^(b)CH₃ ^(a) CH3 COOH 2167 OCH3^(b) CH₃ ^(a) CH3 CH₂OH 2168 OCH3^(b) CH₃^(a) CH3 sugar 2169 OCH3^(b) CH₃ ^(a) CH3 C-glycosyl compound 2170OCH3^(b) CH₃ ^(a) Cl OH 2171 OCH3^(b) CH₃ ^(a) Cl D-glucitol 2172OCH3^(b) CH₃ ^(a) Cl SO₃H 2173 OCH3^(b) CH₃ ^(a) Cl PO₃H₂ 2174 OCH3^(b)CH₃ ^(a) Cl CHO 2175 OCH3^(b) CH₃ ^(a) Cl COOH 2176 OCH3^(b) CH₃ ^(a) ClCH₂OH 2177 OCH3^(b) CH₃ ^(a) Cl sugar 2178 OCH3^(b) CH₃ ^(a) ClC-glycosyl compound 2179 OCH3^(b) CH₃ ^(a) B(OH)₂ OH 2180 OCH3^(b) CH₃^(a) B(OH)₂ D-glucitol 2181 OCH3^(b) CH₃ ^(a) B(OH)₂ SO₃H 2182 OCH3^(b)CH₃ ^(a) B(OH)₂ PO₃H₂ 2183 OCH3^(b) CH₃ ^(a) B(OH)₂ CHO 2184 OCH3^(b)CH₃ ^(a) B(OH)₂ COOH 2185 OCH3^(b) CH₃ ^(a) B(OH)₂ CH₂OH 2186 OCH3^(b)CH₃ ^(a) B(OH)₂ sugar 2187 OCH3^(b) CH₃ ^(a) B(OH)₂ C-glycosyl compound2188 OCH3^(b) CH₃ ^(a) SH OH 2189 OCH3^(b) CH₃ ^(a) SH D-glucitol 2190OCH3^(b) CH₃ ^(a) SH SO₃H 2191 OCH3^(b) CH₃ ^(a) SH PO₃H₂ 2192 OCH3^(b)CH₃ ^(a) SH CHO 2193 OCH3^(b) CH₃ ^(a) SH COOH 2194 OCH3^(b) CH₃ ^(a) SHCH₂OH 2195 OCH3^(b) CH₃ ^(a) SH sugar 2196 OCH3^(b) CH₃ ^(a) SHC-glycosyl compound 2197 OCH3^(b) CH₃ ^(a) OCH3 OH 2198 OCH3^(b) CH₃^(a) OCH3 D-glucitol 2199 OCH3^(b) CH₃ ^(a) OCH3 SO₃H 2200 OCH3^(b) CH₃^(a) OCH3 PO₃H₂ 2201 OCH3^(b) CH₃ ^(a) OCH3 CHO 2202 OCH3^(b) CH₃ ^(a)OCH3 COOH 2203 OCH3^(b) CH₃ ^(a) OCH3 CH₂OH 2204 OCH3^(b) CH₃ ^(a) OCH3sugar 2205 OCH3^(b) CH₃ ^(a) OCH3 C-glycosyl compound 2206 OCH3^(b)OCH3^(b) H OH 2207 OCH3^(b) OCH3^(b) H D-glucitol 2208 OCH3^(b) OCH3^(b)H SO₃H 2209 OCH3^(b) OCH3^(b) H PO₃H₂ 2210 OCH3^(b) OCH3^(b) H CHO 2211OCH3^(b) OCH3^(b) H COOH 2212 OCH3^(b) OCH3^(b) H CH₂OH 2213 OCH3^(b)OCH3^(b) H sugar 2214 OCH3^(b) OCH3^(b) H C-glycosyl compound 2215OCH3^(b) OCH3^(b) OH OH 2216 OCH3^(b) OCH3^(b) OH D-glucitol 2217OCH3^(b) OCH3^(b) OH SO₃H 2218 OCH3^(b) OCH3^(b) OH PO₃H₂ 2219 OCH3^(b)OCH3^(b) OH CHO 2220 OCH3^(b) OCH3^(b) OH COOH 2221 OCH3^(b) OCH3^(b) OHCH₂OH 2222 OCH3^(b) OCH3^(b) OH sugar 2223 OCH3^(b) OCH3^(b) OHC-glycosyl compound 2224 OCH3^(b) OCH3^(b) CH3 OH 2225 OCH3^(b) OCH3^(b)CH3 D-glucitol 2226 OCH3^(b) OCH3^(b) CH3 SO₃H 2227 OCH3^(b) OCH3^(b)CH3 PO₃H₂ 2228 OCH3^(b) OCH3^(b) CH3 CHO 2229 OCH3^(b) OCH3^(b) CH3 COOH2230 OCH3^(b) OCH3^(b) CH3 CH₂OH 2231 OCH3^(b) OCH3^(b) CH3 sugar 2232OCH3^(b) OCH3^(b) CH3 C-glycosyl compound 2233 OCH3^(b) OCH3^(b) Cl OH2234 OCH3^(b) OCH3^(b) Cl D-glucitol 2235 OCH3^(b) OCH3^(b) Cl SO₃H 2236OCH3^(b) OCH3^(b) Cl PO₃H₂ 2237 OCH3^(b) OCH3^(b) Cl CHO 2238 OCH3^(b)OCH3^(b) Cl COOH 2239 OCH3^(b) OCH3^(b) Cl CH₂OH 2240 OCH3^(b) OCH3^(b)Cl sugar 2241 OCH3^(b) OCH3^(b) Cl C-glycosyl compound 2242 OCH3^(b)OCH3^(b) B(OH)₂ OH 2243 OCH3^(b) OCH3^(b) B(OH)₂ D-glucitol 2244OCH3^(b) OCH3^(b) B(OH)₂ SO₃H 2245 OCH3^(b) OCH3^(b) B(OH)₂ PO₃H₂ 2246OCH3^(b) OCH3^(b) B(OH)₂ CHO 2247 OCH3^(b) OCH3^(b) B(OH)₂ COOH 2248OCH3^(b) OCH3^(b) B(OH)₂ CH₂OH 2249 OCH3^(b) OCH3^(b) B(OH)₂ sugar 2250OCH3^(b) OCH3^(b) B(OH)₂ C-glycosyl compound 2251 OCH3^(b) OCH3^(b) SHOH 2252 OCH3^(b) OCH3^(b) SH D-glucitol 2253 OCH3^(b) OCH3^(b) SH SO₃H2254 OCH3^(b) OCH3^(b) SH PO₃H₂ 2255 OCH3^(b) OCH3^(b) SH CHO 2256OCH3^(b) OCH3^(b) SH COOH 2257 OCH3^(b) OCH3^(b) SH CH₂OH 2258 OCH3^(b)OCH3^(b) SH sugar 2259 OCH3^(b) OCH3^(b) SH C-glycosyl compound 2260OCH3^(b) OCH3^(b) OCH3 OH 2261 OCH3^(b) OCH3^(b) OCH3 D-glucitol 2262OCH3^(b) OCH3^(b) OCH3 SO₃H 2263 OCH3^(b) OCH3^(b) OCH3 PO₃H₂ 2264OCH3^(b) OCH3^(b) OCH3 CHO 2265 OCH3^(b) OCH3^(b) OCH3 COOH 2266OCH3^(b) OCH3^(b) OCH3 CH₂OH 2267 OCH3^(b) OCH3^(b) OCH3 sugar 2268OCH3^(b) OCH3^(b) OCH3 C-glycosyl compound ^(a)optionally substitutedwith one, two or three F ^(b)optionally substituted with two or three F

TABLE 4 row number R1 R2 R4 R5 1 ortho ortho 3- ortho 2 ortho ortho 3-meta 3 ortho ortho 3- para 4 ortho ortho 2- ortho 5 ortho ortho 2- meta6 ortho ortho 2- para 7 ortho meta 3- ortho 8 ortho meta 3- meta 9 orthometa 3- para 10 ortho meta 2- ortho 11 ortho meta 2- meta 12 ortho meta2- para 13 ortho para 3- ortho 14 ortho para 3- meta 15 ortho para 3-para 16 ortho para 2- ortho 17 ortho para 2- meta 18 ortho para 2- para19 meta ortho 3- ortho 20 meta ortho 3- meta 21 meta ortho 3- para 22meta ortho 2- ortho 23 meta ortho 2- meta 24 meta ortho 2- para 25 metameta 3- ortho 26 meta meta 3- meta 27 meta meta 3- para 28 meta meta 2-ortho 29 meta meta 2- meta 30 meta meta 2- para 31 meta para 3- ortho 32meta para 3- meta 33 meta para 3- para 34 meta para 2- ortho 35 metapara 2- meta 36 meta para 2- para 37 para ortho 3- ortho 38 para ortho3- meta 39 para ortho 3- para 40 para ortho 2- ortho 41 para ortho 2-meta 42 para ortho 2- para 43 para meta 3- ortho 44 para meta 3- meta 45para meta 3- para 46 para meta 2- ortho 47 para meta 2- meta 48 parameta 2- para 49 para para 3- ortho 50 para para 3- meta 51 para para 3-para 52 para para 2- ortho 53 para para 2- meta 54 para para 2- para

Table 5 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is F, R⁴ is OH and R⁵ is OH (i.e. Table 3, row 1)according to the positions defined by all rows of Table 4.

1 (3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 2(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 3(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 4(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 5(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 6(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 7(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 8(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 9(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 10(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 11(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 12(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 13(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 14(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 15(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 16(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 17(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one 18(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Table 6 lists the compounds disclosed by substitution of Formula VIIIwhere R¹ is H, R² is F, R⁴ is OH and R⁵ is D-glucitol (i.e. Table 3, row2) according to the positions defined by all rows of Table 4.

1(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol 2(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol 3(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol 4(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol 5(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol 6(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol 7(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol 8(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol 9(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol 10(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol 11(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol 12(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol 13(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol 14(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol 15(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol 16(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol 17(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol 18(1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol

Table 7 lists the compounds disclosed by substitution of Formula VIIIwherein R is H, R² is F, R⁴ is OH and R⁵ is SO₃H (i.e. Table 3, row 3)according to the positions defined by all rows of Table 4.

14′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 24′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 34′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 44′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 54′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 64′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid 74′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 84′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 94′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 104′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 114′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 124′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid 134′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 144′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 154′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 164′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 174′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 184′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid

Table 8 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is F, R⁴ is OH and R⁵ is PO₃H₂ (i.e. Table 3, row 4)according to the positions defined by all rows of Table 4.

1(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid 2(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid 3(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid 4(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid 5(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid 6(4′-{(2S,3R)-3-[(3S)-3-(2-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid 7(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid 8(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid 9(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid 10(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid 11(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid 12(4′-{(2S,3R)-3-[(3S)-3-(3-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid 13(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid 14(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid 15(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid 16(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid 17(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid 18(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid

Table 9 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is H, R⁴ is OH and R⁵ is OH (i.e. Table 3, row 5)according to the positions defined by all rows of Table 4.

1 (3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]- 1-phenylazetidin-2-one 2(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]- 1-phenylazetidin-2-one 3(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]- 1-phenylazetidin-2-one 4(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]- 1-phenylazetidin-2-one 5(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]- 1-phenylazetidin-2-one 6(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-hydroxy-3-phenylpropyl]- 1-phenylazetidin-2-one

Table 10 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is H, R⁴ is OH and R⁵ is D-glucitol (i.e. Table 3,row 6) according to the positions defined by all rows of Table 4.

1 (1S)-1,5-anhydro-1-(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-yl)-D-glucitol 2(1S)-1,5-anhydro-1-(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol 3(1S)-1,5-anhydro-1-(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol 4(1S)-1,5-anhydro-1-(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-yl)-D-glucitol 5(1S)-1,5-anhydro-1-(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol 6(1S)-1,5-anhydro-1-(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol

Table 11 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is H, R⁴ is OH and R⁵ is SO₃H (i.e. Table 3, row 7)according to the positions defined by all rows of Table 4.

1 3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-sulfonic acid 23′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-sulfonic acid 33′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-sulfonic acid 42′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-sulfonic acid 52′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-sulfonic acid 62′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-sulfonic acid

Table 12 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is H, R⁴ is OH and R⁵ is PO₃H₂ (i.e. Table 3, row 8)according to the positions defined by all rows of Table 4.

1 (3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-yl)phosphonic acid 2(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid 3(3′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)phosphonic acid 4(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-2-yl)phosphonic acid 5(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonic acid 6(2′-hydroxy-4′-{(2S,3R)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-4-yl)phosphonic acid

Table 13 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is Cl, R⁴ is OH and R⁵ is OH (i.e. Table 3, row 9)according to the positions defined by all rows of Table 4.

1(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one2(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one3(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one4(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one5(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one6(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one7(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one8(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one9(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one10(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one11(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-cjlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one12(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one13(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one14(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one15(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one16(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one17(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one18(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4chlorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one

Table 14 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is Cl, R⁴ is OH and R⁵ is D-glucitol (i.e. Table 3,row 10) according to the positions defined by all rows of Table 4.

1 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol2 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol3 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol4 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol5 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol6 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol7 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol8 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol9 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol10 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol11 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol12 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol13 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)-D-glucitol14 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol15 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)-D-glucitol16 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)-D-glucitol17 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)-D-glucitol18 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)-D-glucitol

Table 15 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is Cl, R⁴ is OH and R⁵ is SO₃H (i.e. Table 3, row11) according to the positions defined by all rows of Table 4.

1 4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 24′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 34′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 44′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 54′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 64′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid 74′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 84′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 94′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 104′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 114′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 124′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid 134′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 144′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 154′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 164′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 174′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 184′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid

Table 16 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is H, R² is Cl, R⁴ is OH and R⁵ is PO₃H₂ (i.e. Table 3, row12) according to the positions defined by all rows of Table 4.

1 (4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid 2(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid 3(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid 4(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid 5(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid 6(4′-{(2S,3R)-3-[(3S)-3-(2-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid 7(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid 8(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid 9(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid 10(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid 11(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid 12(4′-{(2S,3R)-3-[(3S)-3-(3-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid 13(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonic acid 14(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonic acid 15(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonic acid 16(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonic acid 17(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonic acid 18(4′-{(2S,3R)-3-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonic acid

Table 17 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is F, R² is H, R⁴ is OH and R⁵ is OH (i.e. Table 3, row 13)according to the positions defined by all rows of Table 4.

1 (3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 2(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 3(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 4(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 5(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 6(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 7(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 8(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 9(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 10(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 11(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 12(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 13(3R,4S)-4-(2′,3-dihydroxybiphenyl-4-yl)-1- (4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 14(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-1- (4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 15(3R,4S)-4-(3,4′-dihydroxybiphenyl-4-yl)-1- (4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 16(3R,4S)-4-(2,2′-dihydroxybiphenyl-4-yl)-1- (4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 17(3R,4S)-4-(2,3′-dihydroxybiphenyl-4-yl)-1- (4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one 18(3R,4S)-4-(2,4′-dihydroxybiphenyl-4-yl)-1- (4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]azetidin-2-one

Table 18 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is F, R² is H, R⁴ is OH and R⁵ is D-glucitol (i.e. Table 3,row 14) according to the positions defined by all rows of Table 4.

1 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)- D-glucitol 2(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)- D-glucitol 3(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)- D-glucitol 4(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)- D-glucitol 5(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)- D-glucitol 6(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)- D-glucitol 7(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)- D-glucitol 8(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)- D-glucitol 9(1S)-1,5-anhydro-1-(4′-{(2S,3R)-1- (3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)- D-glucitol10 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)- D-glucitol11 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)- D-glucitol12 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)- D-glucitol13 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)- D-glucitol14 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)- D-glucitol15 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)- D-glucitol16 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)- D-glucitol17 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)- D-glucitol18 (1S)-1,5-anhydro-1-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)- D-glucitol

Table 19 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is F, R² is H, R⁴ is OH and R⁵ is SO₃H (i.e. Table 3, row 15)according to the positions defined by all rows of Table 4.

1 4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 24′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 34′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 44′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 54′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 64′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid 74′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 84′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 94′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 104′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 114′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 124′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid 134′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-sulfonic acid 144′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonic acid 154′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonic acid 164′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-sulfonic acid 174′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-sulfonic acid 184′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-sulfonic acid

Table 20 lists the compounds disclosed by substitution of Formula VIIIwherein R¹ is F, R² is H, R⁴ is OH and R⁵ is PO₃H₂ (i.e. Table 3, row16) according to the positions defined by all rows of Table 4.

1(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonicacid 2(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonicacid 3(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonicacid 4(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonicacid 5(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonicacid 6(4′-{(2S,3R)-1-(2-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonicacid 7(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonicacid 8(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonicacid 9(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonicacid 10(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonicacid 11(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonicacid 12(4′-{(2S,3R)-1-(3-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonicacid 13(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-2-yl)phosphonicacid 14(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)phosphonicacid 15(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-3′-hydroxybiphenyl-4-yl)phosphonicacid 16(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-2-yl)phosphonicacid 17(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-3-yl)phosphonicacid 18(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-hydroxy-3-phenylpropyl]-4-oxoazetidin-2-yl}-2′-hydroxybiphenyl-4-yl)phosphonicacid

1-139. (canceled)
 140. A compound of formula

wherein R^(1i) and R^(2i) are chosen from H, Cl and F; and R^(5i) ischosen from OH and SO₃H.
 141. A compound according to claim 140 offormula

wherein the substituent at position 3 of the azetidin-2-one is of the Rabsolute configuration, the substituent at position 4 of theazetidin-2-one is of the S absolute configuration and the benzylichydroxyl is of the S absolute configuration.
 142. A compound accordingto claim 141 wherein R^(5i) is OH. 143.(3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-oneaccording to claim
 142. 144. A compound according to claim 141 whereinR^(5i) is SO₃H. 145.4′-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-sulfonicacid;4′-{(2S,3R)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-sulfonicacid; or4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonicacid according to claim
 144. 146. Sodium4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-4-sulfonate.147. A pharmaceutical formulation comprising a compound according toclaim 140 and a pharmaceutically acceptable carrier.
 148. Apharmaceutical formulation according to claim 147 additionallycomprising an inhibitor of cholesterol biosynthesis.
 149. A method fortreating a disorder of lipid metabolism comprising administering to amammal a therapeutically effective amount of a compound having theformula shown in claim 140, wherein said disorder is chosen fromhypercholesterolemia, hyperlipidemia, arteriosclerosis andsitosterolemia.
 150. A pharmaceutical formulation according to claim 148wherein said inhibitor of cholesterol biosynthesis is an HMG-CoAreductase inhibitor.
 151. A pharmaceutical formulation according toclaim 150 wherein said HMG-CoA reductase inhibitor is chosen from thegroup consisting of lovastatin, simvastatin, pravastatin, rosuvastatin,mevastatin, atorvastatin, cerivastatin, pitavastatin, fluvastatin,bervastatin, crilvastatin, carvastatin, rivastatin, sirrivastatin,glenvastatin and dalvastatin.
 152. A pharmaceutical formulationaccording to claim 147 additionally comprising at least one bile acidsequestrant.
 153. A pharmaceutical formulation according to claim 152wherein the at least one bile acid sequestrant is selected from thegroup consisting of cholestyramine, colestipol, colesevelamhydrochloride and mixtures thereof.
 154. A pharmaceutical formulationaccording to claim 147 additionally comprising at least one nicotinicacid or derivative thereof selected from the group consisting ofnicotinic acid, niceritrol, nicofuranose, acipimox and mixtures thereof.155. A pharmaceutical formulation according to claim 147 additionallycomprising at least one peroxisome proliferator-activated receptor alphaactivator.
 156. A pharmaceutical formulation according to claim 155wherein said peroxisome proliferator-activated receptor alpha activatoris a fibric acid derivative.
 157. A pharmaceutical formulation accordingto claim 156 wherein said fibric acid derivative is selected from thegroup consisting of fenofibrate, clofibrate, gemfibrozil, ciprofibrate,bezafibrate, clinofibrate, binifibrate, lifibrol and mixtures thereof.158. A pharmaceutical formulation according to claim 147 additionallycomprising at least one cholesterol ester transfer protein (CETP)inhibitor.
 159. An article of manufacture comprising a container,instructions, and a pharmaceutical formulation according to claim 147,wherein the instructions are for the administration of thepharmaceutical formulation for a purpose chosen from: the prevention ortreatment of a disorder of lipid metabolism; reducing the plasma ortissue concentration of at least one 5α-cholestanol or cholest-5-enolother than (3β)-cholest-5-ene-3-ol; reducing the blood plasma or serumconcentrations of LDL cholesterol; reducing the concentrations ofcholesterol and cholesterol ester in the blood plasma or serum;increasing the fecal excretion of cholesterol; reducing the incidence ofcoronary heart disease-related events; reducing blood plasma or serumconcentrations of C-reactive protein (CRP); treating or preventingvascular inflammation; reducing blood plasma or serum concentrations oftriglycerides; increasing blood plasma or serum concentrations of HDLcholesterol; reducing blood plasma or serum concentrations ofapolipoprotein B.
 160. A method according to claim 149, wherein saiddisorder of lipid metabolism is hyperlipidemia.
 161. A method accordingto claim 149, wherein said disorder of lipid metabolism isarteriosclerosis.
 162. A method according to claim 149, wherein saiddisorder of lipid metabolism is sitosterolemia.
 163. A method forinhibiting the absorption of cholesterol from the intestine of a mammal,which comprises administering an effectivecholesterol-absorption-inhibiting amount of a compound according toclaim 140 to the mammal.
 164. A method of reducing plasma or tissueconcentration of at least one 5α-cholestanol or cholest-5-enol otherthan (3β)-cholest-5-ene-3-ol, comprising administering to a mammal inneed of such treatment an effective amount of a compound according toclaim
 140. 165. A method for reducing the blood plasma or serumconcentrations of LDL cholesterol in a mammal, which comprisesadministering an effective cholesterol reducing amount of a compoundaccording to claim 140 to the mammal.
 166. A method for reducing theconcentrations of cholesterol and cholesterol ester in the blood plasmaor serum of a mammal, which comprises administering an effectivecholesterol and cholesterol ester reducing amount of a compoundaccording to claim 140 to the mammal.
 167. A method for increasing thefecal excretion of cholesterol in a mammal, which comprisesadministering an effective cholesterol fecal excretion increasing amountof a compound according to claim 140 to the mammal.